self-replicating RNA molecule, alphavirus replicon particle, composition, recombinant DNA molecule,

专利摘要:
ANTIGEN RELEASE PLATFORMS This disclosure provides platforms for the release of herpesvirus proteins to cells, particularly proteins that form complexes in vivo. In some modalities, these proteins and the complexes they form arouse potent neutralizing antibodies. Thus, the presentation of herpesvirus proteins using the revealed platforms allows the generation of broad and potent immune responses useful for the development of vaccines,
公开号:BR112013008700B1
申请号:R112013008700-5
申请日:2011-10-11
公开日:2021-03-02
发明作者:Anders Lilja；Rebecca Loomis；Michael Franti；Peter Mason
申请人:Novartis Ag；
IPC主号:

专利说明:

RELATED ORDER
[0001] This application claims the benefit of U.S. Provisional Patent Application No. 61 / 391,960, filed on October 11, 2010, the teachings of which are hereby incorporated by reference. BACKGROUND OF THE INVENTION
[0002] Herpes viruses are widespread and cause a wide range of diseases in humans that, in the worst cases, can lead to substantial morbidity and mortality, primarily in immunocompromised individuals (for example, transplant recipients and HIV-infected individuals). Humans are susceptible to infection with at least eight herpesviruses. Herpes simplex virus-1 (HSV-1, HHV-1), herpes simplex virus-2 (HSV-2, HHV-2) and varicella zoster virus (VZV, HHV-3) are viruses of the alpha subfamily , cytomegalovirus (CMV, HHV-5) and roseolovirus (HHV-6 and HHV-7) are viruses of the beta subfamily, Epstein-Barr virus (EBV, HHV-4) and herpesvirus associated with Kaposi's sarcoma (KSHV, HHV-8) are viruses of the gamma subfamily that infect humans.
[0003] CMV infection leads to substantial morbidity and mortality in immunocompromised individuals (for example, transplant recipients and HIV-infected individuals), and congenital infection can result in devastating defects in neurological development in neonates. The glycoproteins of the CMV envelope gB, gH, gL, gM and gN represent attractive vaccine candidates, as they are expressed on the viral surface and can awaken protective humoral immune responses neutralizing viruses. Some vaccine strategies for CMV targeted the main surface glycoprotein B (gB), which can induce a dominant antibody response (Go and Pollard, JID 197: 1.631-1.633 (2008)). The CMV gB glycoprotein can induce a neutralizing antibody response, and a large fraction of the antibodies that neutralize fibroblast infection in sera from CMV-positive patients are directed against gB (Britt 1990). Similarly, gH and gM / gN have been reported to be targets of the immune response to natural infection (Urban et al. (1996) J. Gen. Virol. 77 (Part 7): 1.537-47; Mach et al. (2000) J Virol. 74 (24): 11.881-92).
[0004] CMV protein complexes are also attractive vaccine candidates, as they appear to be involved in important processes in the viral life cycle. For example, the gH / gL / gO complex appears to play important roles in entry into both fibroblasts and epithelial / endothelial cells. The prevailing model suggests that the gH / gL / gO complex mediates fibroblast infection. hCMV gO-null mutants produce small fibroblast plaques and very low virus titration, indicating a role at entry (Dunn (2003), Proc. Natl. Acad. Sci. USA 100: 14.223-28; Hobom (2000) J. Virol 74: 7.720-29). Recent studies suggest that gO is not incorporated into virions with gH / gL, but can act as a molecular chaperone, increasing the export of gH / gL from the ER to the Golgi apparatus and incorporation into virions (Ryckman (2009) J. Virol. 82: 60-70). Through pulse-chase experiments, it has been shown that small amounts of gO remain bound to gH / gL for long periods of time, but most of the gO dissociates and / or degrades the gH / gL / complex gO, since it is not found in extracellular virions or secreted by cells. When gO was deleted from a clinical strain of CMV (TR), those viral particles had significantly reduced amounts of gH / gL incorporated into the virus. In addition, deleted gO from the TR virus also inhibited entry into epithelial and endothelial cells, suggesting that gH / gL is also required for entry into the epithelial / endothelial cell (Wille (2010) J. Virol. 84 (5): 2.585-96) .
[0005] CMV gH / gL can also be associated with UL128, UL130 and UL131A (here called UL131) and form a pentameric complex that is required for entry into various types of cells, including epithelial cells, endothelial cells and dendritic cells (Hahn et al (2004) J. Virol. 78 (18): 10.023-33; Wang and Shenk (2005) Proc. Natl. Acad. Sci. USA 102 (50): 18.153-8; Gerna et al. (2005) J. Gen. Virol. 84 (Part 6): 1.431-6; Ryckman et al (2008) J. Virol. 82: 60-70). In contrast, this complex is not necessary for infection of fibroblasts. Laboratory isolates of hCMV carry mutations at the UL128-UL131 locus, and mutations appear in clinical isolates after few passages in cultured fibroblasts (Akter et al (2003) J. Gen. Virol. 84 (Part 5): 1.117-22). During natural infection, the pentameric complex awakens antibodies that neutralize the infection of epithelial cells, endothelial cells (and probably any other type of cell in which the pentameric complex mediates viral entry) with very high potency (Macagno et al. (2010 ) J. Virol. 84 (2): 1.005-13). It also appears that antibodies to this complex contribute significantly to the ability of human sera to neutralize infection of epithelial cells (Genini et al (2011) J. Clin. Virol. 52 (2): 113-8).
[0006] US 5,767,250 discloses methods for the production of certain CMV protein complexes that contain gH and gL. The complexes are produced by introducing a DNA construct that encodes gH and a DNA construct that encodes gL into a cell in such a way that gH and gL are co-expressed.
[0007] WO 2004/076645 describes recombinant DNA molecules that encode CMV proteins. According to that document, combinations of distinct DNA molecules that encode different CMV proteins can be introduced into cells to cause co-expression of the encoded CMV proteins. When gM and gN were co-expressed in this way, they formed a disulfide-linked complex. Rabbits immunized with DNA constructs that produced the gM / gN complex or with a DNA construct encoding gB produced equivalent neutralizing antibody responses.
[0008] There is a need for nucleic acids that encode two or more herpesvirus proteins, for methods of expressing two or more herpesvirus proteins in the same cell and for immunization methods that produce better immune responses. SUMMARY OF THE INVENTION
[0009] The invention relates to the platforms for the coliberation of two or more herpesvirus proteins, for example, cytomegalovirus (CMV) proteins, to cells, particularly proteins that form complexes in vivo. In one aspect, the invention consists of recombinant polycistronic nucleic acid molecules that contain a first sequence that encodes a first herpesvirus protein (for example, CMV) or fragment thereof, and a second sequence that encodes a second herpesvirus protein (for example , CMV) or fragment thereof.
For example, the invention provides a self-replicating RNA molecule comprising a polynucleotide comprising: a) a first nucleotide sequence that encodes a first protein or fragment thereof from a herpesvirus; and b) a second nucleotide sequence that encodes a second herpesvirus protein, or fragment thereof. The first nucleotide sequence and the second nucleotide sequence are operationally linked to one or more control elements so that when the self-replicating RNA molecule is introduced into a suitable cell, the first and second herpesvirus proteins, or fragments thereof, are produced in an amount sufficient to form a complex in the cell containing the first and second proteins, or fragments thereof. Preferably, the first protein and the second protein are not the same protein or fragments of the same protein, the first protein is not a fragment of the second protein and the second protein is not a fragment of the first protein. The first nucleotide sequence can be operationally linked to a first control element and the second nucleotide sequence can be operationally linked to a second control element.
The self-replicating RNA molecule may further comprise a third nucleotide sequence that encodes a third protein, or fragment thereof, from said herpesvirus, optionally a fourth nucleotide sequence encoding a fourth protein, or fragment thereof, from said herpesvirus; and, optionally, a fifth nucleotide sequence that encodes a fifth protein, or fragment thereof, of said herpesvirus. When sequences encoding additional proteins or fragments of a herpes virus are present (ie, the third, fourth and fifth nucleotide sequences), they are operationally linked to one or more control elements. In an example of a pentacistronic construction, the first nucleotide sequence is operationally linked to a first control element, the second nucleotide sequence is operationally linked to a second control element, the third nucleotide sequence is operationally linked to a third element control, the fourth nucleotide sequence is operationally linked to a fourth control element and the fifth nucleotide sequence is operationally linked to a fifth control element. The control elements present in the construction (for example, first, second, third, fourth and fifth control elements) can be selected independently from the group consisting of a subgenomic promoter, an IRES and a viral 2A site (for example, FMDV) .
[0012] Herpesvirus can be HSV-1, 1, HSV-2, VZV, EBV type 1, EBV type 2, CMV, HHV-6 type A, HHV-6 type B, HHV-7 and HHV-8. In some embodiments, the recombinant polycistronic nucleic acid molecule (e.g., self-replicating RNA) encodes gH or a fragment thereof and gL or a fragment thereof from any of these herpesviruses. In more particular modalities, herpesvirus is CMV or VZV.
[0013] When the recombinant polycistronic nucleic acid molecule (eg, self-replicating RNA) encodes two or more VZV proteins, the proteins can be selected from the group consisting of gB, gE, gH, gI, gL and a fragment (for example, from at least 10 amino acids) of these. In some embodiments, the recombinant polycistronic nucleic acid molecule (e.g., self-replicating RNA) encodes VZV gH or a fragment thereof and VZV gL or a fragment thereof.
[0014] In a particular example, the invention provides a self-replicating RNA molecule comprising a polynucleotide comprising: a) a first sequence that encodes a first cytomegalovirus (CMV) protein or fragment thereof; and b) a second sequence that encodes a second CMV protein or fragment thereof. The first sequence and the second sequence are operationally linked to one or more control elements in such a way that when the self-replicating RNA molecule is introduced into a suitable cell, the first and second CMV proteins are produced in an amount sufficient for the formation of a complex in the cell that contains the first and second CMV proteins, or fragments thereof.
[0015] The first CMV protein and the second CMV protein are selected independently from the group consisting of gB, gH, gL; gO; gM, gN; UL128, UL130, UL131, and a fragment of any of those mentioned above. Preferably, the first CMV protein and the second CMV protein are not the same protein or fragments of the same protein, the first CMV protein is not a fragment of the second CMV protein, and the second CMV protein is not a fragment of the first CMV protein. If desired, the self-replicating RNA molecule may further comprise a third sequence that encodes a third CMV protein, in which the third sequence is operably linked to a control element. Similarly, additional sequences that encode additional CMV proteins (for example, a fourth sequence that encodes a fourth CMV protein, a fifth sequence that encodes a fifth CMV protein) can be included. Control elements can be selected independently from the group consisting of a subgenomic promoter, and IRES, and a 2A viral site.
[0016] In some embodiments, the self-replicating nucleic acid molecule encodes the CMV gH and gL proteins. In other embodiments, the self-replicating RNA molecule encodes the CMV proteins gH, gL and gO. In other embodiments, the self-replicating RNA molecule encodes the CMV proteins gH, gL, UL128, UL130 and UL131.
[0017] The self-replicating RNA molecules can be an alphavirus replicon. In such cases, the alphavirus replicon can be released in the form of an alphavirus replicon (VRP) particle. The self-replicating RNA molecule can also be in the form of a “naked” RNA molecule.
[0018] The invention also relates to a recombinant DNA molecule that encodes a self-replicating RNA molecule as described herein. In some embodiments, the recombinant DNA molecule is a plasmid. In some embodiments, the recombinant DNA molecule includes a mammalian promoter that directs the transcription of the encoded self-replicating RNA molecule.
[0019] The invention also relates to compositions that comprise a self-replicating RNA molecule as described herein and a pharmaceutically acceptable carrier. The self-replicating RNA molecule can be "naked". In some embodiments, the composition comprises a self-replicating RNA molecule that encodes the CMV gH and gL proteins. In other embodiments, the composition further comprises a self-replicating RNA molecule that encodes the CMV gB protein. The composition may also contain an RNA delivery system, such as a liposome, a polymeric nanoparticle, a cationic oil-in-water nanoemulsion, or combinations thereof. For example, the self-replicating RNA molecule can be encapsulated in a liposome.
[0020] In certain embodiments, the composition comprises a VRP that contains the alphavirus replicon that encodes two or more CMV proteins. In some embodiments, the VRP comprises a replicon that encodes CMV gH and gL. If desired, the composition may further comprise a second VRP that contains a replicon that encodes CMV gB. The composition can also comprise an adjuvant.
[0021] The invention is also related to the methods of forming a CMV protein complex. In some embodiments, a self-replicating RNA that encodes two or more CMV proteins is released to a cell, the cell is maintained under conditions suitable for the expression of CMV proteins, in which a CMV protein complex is formed. In other embodiments, a VRP that contains a self-replicating RNA that encodes two or more CMV proteins is released to a cell, the cell is maintained under conditions suitable for the expression of CMV proteins, in which a CMV protein complex is formed. The method can be used to form a CMV protein complex in a cell in vivo.
[0022] The invention is also related to a method for inducing an immune response in an individual. In some embodiments, a self-replicating RNA that encodes two or more CMV proteins is administered to the individual. The self-replicating RNA molecule can be administered as a composition that contains an RNA delivery system, for example, a liposome. In other embodiments, a VRP that contains a self-replicating RNA that encodes two or more CMV proteins is administered to the individual. In preferred embodiments, the self-replicating RNA molecule encodes CMV proteins gH and gL. Preferably, the induced immune response comprises the production of neutralizing anti-CMV antibodies. Most preferably, the neutralizing antibodies are complement-independent.
[0023] The invention also relates to a method of inhibiting CMV entry into a cell that comprises contacting the cell with a self-replicating RNA molecule that encodes two or more CMV proteins, for example, gH and gL. The cell can be selected from the group consisting of an epithelial cell, an endothelial cell, a fibroblast, and combinations of these. In some embodiments, the cell is placed in contact with a VRP that contains a self-replicating RNA that encodes two or more CMV proteins.
[0024] The invention also relates to the use of a self-replicating RNA molecule that encodes two or more CMV proteins (for example, a VRP, a composition comprising the self-replicating RNA molecule and a liposome) to form a complex of CMV proteins in a cell, to induce an immune response or to inhibit the entry of CMV into a cell. BRIEF DESCRIPTION OF THE DRAWINGS
[0025] FIG. 1 is a schematic representation of CMV that identifies known glycoprotein complexes involved in the entry of CMV into target cells. Envelope glycoproteins represent attractive vaccine candidates as they are expressed on the viral surface and can elicit protective, long-lasting humoral immune responses. The structural glycoproteins that mediate these processes can be divided into two classes; those that are preserved in the entire family of herpesviruses and those that are not. Among those that are conserved are gB, gH, gL, gM and gN. Many of these glycoproteins form complexes between them (gH / gL / ± gO; gH / gL / UL128 / UL130 / UL131; gM / gN) to facilitate localization on the viral surface and to perform their functions in viral adhesion, entry and cell fusion .
[0026] FIGS. 2A-2F are schematic representations of CMV constructions. FIG. 2A, schematic representation of the gB constructions ("gB FL", full length gB; soluble gBs "gB sol 750" and "gB sol 692") described in Example 1. Two different soluble versions of gB were constructed; gB sol 750 does not have the transmembrane expansion domain and the cytoplasmic domain, gB sol 692 also does not have a hydrophobic region and is similar to the gB sol described in Reap et al. (2007) Clin. Vacc. Immunol. 14: 748-55. FIG. 2B, schematic representation of the gB replicon vectors used to produce viral replication particles (VRPs). FIG. 2C, schematic representation of the gH constructions ("gH FL", full length gH; soluble gH "gH sol") described in Example 1. A single soluble version of gH was constructed that lacked the transmembrane expansion domain. FIG. 2D, schematic representation of the gH replicon vectors used to produce VRPs. FIG. 2E, schematic representation of the gL construction described in Example 1. FIG. 2F, schematic representation of the gL replicon vector used to produce VRPs. In FIGS 2B, 2D and 2F, "NSP1", "NSP2", "NSP3" and "NSP4", are non-structural alphavirus proteins 1-4, respectively, necessary for virus replication.
[0027] FIGS. 3A and 3B show that mice immunized with VRPs from gB (FL, sol 750, sol 692) or gH (FL, sol) induced antibody responses that were neutralizing in the presence of guinea pig complement. The neutralization assay was performed by pre-incubation of the CMV virus strain TB40UL32E-GFP (which encodes the enhanced green fluorescent protein-GFP, Sampaio et al (2005) J. Virol. 79 (5): 2.754-67), with mouse sera and guinea pig complement prior to infection of ARPE-19 epithelial cells. Five days post-infection, the number of GFP-positive cells was determined. FIG. 3A, Serum dilution curve for all sera analyzed in ARPE-19 cells in the presence of complement. FIG. 3B, 50% neutralization titrations for serum samples. Viruses incubated with pre-immune sera generated low neutralization at low dilutions (1: 40-1: 80). GB sera (FL, sol 750, sol 692) had very low neutralizing activity with 50% neutralization titrations between 1: 1,800-1: 2,100. All mice immunized with gB generated a similar neutralization profile. GH sera (FL, sol) had neutralizing activity with titrations of 50% neutralization around 1: 160. See Example 1.
[0028] FIG. 4A is a schematic illustration of repliconmonocistronic that encodes green fluorescent protein (GFP) or red fluorescent protein (mCherry) and the bicistronic replicon that encodes GFP and mCherry. "NSP1", "NSP2", "NSP3" and "NSP4", are non-structural alphavirus proteins 1-4, respectively. The polycistronic alphavirus replicon system was designed by making modifications to the existing alphavirus replicon system to accommodate multiple subgenomic promoters that drive genes of interest.
[0029] FIG. 4B are fluorescence plots showing FACS analysis of BHKV cells infected with VRPs containing mono- and bicistronic RNAs. Polycistronic alphavirus VRPs generate more cells that express both genes of interest in approximately equal amounts (GFP and mCherry; 72.48%) than the VRF co-infection of GFP + VRP of mCherry (26.30%). See Example 2.
[0030] FIG. 5A is a schematic illustration of construction of polycistronic alphavirus replicon constructs encoding gH / gL and gH / gL / gO.
[0031] FIG. 5B shows that gH / gL form a complex in vitro. VRPs containing replicons encoding gH, gL, gO, gH / gL or gH / gL / gO were produced in BHKV cells. The resulting VRPs were used to infect ARPE-19 cells to demonstrate complex formation in vitro. The alphavirus-infected ARPE-19 cells were collected and analyzed for the presence of gH and gL. ARPE-19 cells infected with VRPs encoding gH / gL produced disulfide-linked gH / gL complexes (see in the absence of DTT, heat). gO does not alter the detectable form of the gH / gL association. The graph on the left shows the expression of the gH protein. The graph on the right shows gL protein expression. Molecular weight markers are indicated between the graphs. • = monomeric gH, •• = monomeric gL, <= heterodimer (gH + gL), * = heterodimer dimer.
[0032] FIG. 5C shows immunoprecipitation of gH and gH / gL complexes of BHKV cells infected with VRPs. Immunoprecipitation was performed using mouse IgG antibodies as a control (Rays 2, 4, 7 and 10) or anti-mouse gH antibodies (Genway) to immunoprecipitate gH (Rays 3, 5, 8 and 11). Western blots were performed using pooled rabbit anti-gL antibody and pooled rabbit anti-gH antibody. Rays 1, 6 and 9 show the gH protein (upper band approximately 75 kDa) and gL protein (lower band approximately 30 kDa) for reference. Lanes 2 and 3 are lysates infected with gH-VRP. Lane 2 shows that the control antibody did not immunoprecipitate gH. Lane 3 shows that the anti-gH antibody immunoprecipitated gH. Lanes 4 and 5 are from lysates infected with gL-VRP only. No gH protein was immunoprecipitated. Lanes 7 and 8 are from lysates infected with bicistronic gH / gL-VRP. Lane 8 shows that gL was immunoprecipitated using the gH antibody. (see the asterisk). Lanes 10 and 11 are from lysates infected with tristristronic gH / gL / gO-VRP. Lane 11 shows that gL was immunoprecipitated using the gH antibody (see asterisk). Molecular weight markers are also shown (MW). See Example 3.
[0033] FIG. 6 shows that VRPs that affect the formation of the gH / gL complex in vitro induce a potent immune response to CMV that is qualitatively and quantitatively superior to the response to gB VRPs. FIG. 6A and FIG. 6B show serum dilution curves for mice immunized with gH, gL, gO, gH + gL, gH + gL + gO, gH / gL and gH / gL / gO VRP in neutralizing TB40-UL32-EGFP cell infection ARPE-19 in the presence (FIG. 6A) or absence (FIG. 6B) of complement. Various dilutions of sera were pre-incubated with TB40UL32E-GFP in the presence or absence of guinea pig complement and then added to the ARPE-19 epithelial cells. After 5 days of infection with the virus, GFP-positive cells were counted. FIG. 6C is a graph showing 50% neutralization titrations obtained in the presence and absence of complement. “3wp3”, three weeks after the third immunization. VRPs expressing single CMV proteins (gH, gL, gO VRPs or gH, gL and gO VRPs co-administered) do not increase neutralizing activity beyond that of gH alone. In contrast, mouse sera immunized with gH / gL bicistronic or gH / gL / gO tricistronic VRPs demonstrated potent neutralizing responses. In addition, the potent neutralizing responses were similar in the presence and absence of guinea pig complement, showing that polycistronic VRPs successfully induced a complement-independent immune response. See Example 4.
[0034] FIG. 7 shows that VRPs that affect the formation of the gH / gL complex in vitro induced antibodies that potently neutralized the infection of MRC-5 fibroblast cells. FIG. 7A shows serum dilution curves for mice immunized with VRP of gH, gL, gO, gH + gL, gH + gL + gO, gH / gL and gH / gL / gO in MRC-5 cells in the absence of complement. Various dilutions of sera were pre-incubated with TB40GFP in the presence or absence of guinea pig complement and then added to the MRC-5 fibroblast cells. After 5 days of infection with the virus, GFP-positive cells were counted. FIG. 7B is a graph showing 50% neutralization titrations obtained in a fibroblast cell model MRC-5 in the absence of complement. “3wp3”, three weeks after the third immunization. VRPs expressing single CMV proteins (gH, gL, gO VRPs or gH, gL and gO VRPs co-administered) do not increase neutralizing activity beyond that of gH alone. In contrast, mouse sera immunized with gH / gL bicistronic or gH / gL / gO tricistronic VRPs demonstrated extremely potent neutralizing responses. See Example 4.
[0035] FIGS. 8A and 8B are graphs showing that the neutralizing antibodies induced by the release of polycistronic VRPs were cross-neutralizing antibodies. Sera from mice immunized with gH / gL and VRH from gH / gL / gO were able to neutralize clinical strains of CMV TB40UL32E-GFP and VR1814 both in ARPE-19 epithelial cells (FIG. 8A) and in MRC-5 fibroblast cells (FIG. 8B) in the absence of guinea pig complement in an IE-1 neutralization assay.
[0036] FIG. 9 is a graph that shows that the neutralizing antibodies developed against gH FL / gL are complement-independent and similar to natural immunity in the titration. The mice were immunized with VRPs of gB FL or gH FL / gL at 1 x 10 6 IU, 3 times, with an interval of 3 weeks before terminal bleeding. Sera were analyzed for ability to neutralize CMV TB40UL32E-EGFP infection of ARPE-19 cells in the presence and absence of guinea pig complement in a deneutralization assay. Differentiated antibodies developed by gB, antibodies developed by gH FL / gL are complement-independent. In addition, the gH FL / gL antibodies in these vaccinated mice were similar in terms of titration to those found in naturally infected human subjects.
[0037] AFIG.10 shows a map of plasmid video for SG-SGPgL-SGPgO modified by pVCR.
[0038] AFIG.11 shows a map of plasmid video for SG-SGPgL modified by pVCR.
[0039] FIG. 12 shows a plasmid map for pVCR-modified gH sol-SGPgL.
[0040] FIG. 13 shows a plasmid map for pVCR-modified gH sol-SGPgL-SGPgO.
[0041] FIG. 14A-14G show the nucleotide sequence (SEQ ID. NO: 83) of the plasmid encoding the A160 self-replicating RNA molecule encoding CMV H surface glycoprotein (gH) and CMV L surface glycoprotein ( gL). The nucleotide sequences encoding gH and gL are underlined.
[0042] FIG. 15A-15H show the nucleotide sequence (SEQ ID. NO: 84) of the plasmid encoding the A322 self-replicating RNA molecule encoding the soluble form of CMV H surface glycoprotein (gH sol) and glycoprotein from surface of CMV L (gL). The nucleotide sequences encoding gH sol and gL are underlined.
[0043] FIG. 16A-16H show the nucleotide sequence (SEQ ID. NO: 85) of the plasmid encoding the A323 self-replicating RNA molecule encoding the CMV B surface glycoprotein (gB). The nucleotide sequence encoding gB is underlined.
[0044] FIG. 17A and 17B are histograms showing 50% neutralizing titrations of mouse sera that have been immunized with VRP or self-replicating RNA. FIG. 17A shows 50% neutralizing titrations against human CMV strain TB40UL32E-EGFP (TB40) in ARPE-19 cells, and FIG. 17B shows 50% neutralizing titrations against human CMV strain 8819 in ARPE-19 cells.
[0045] FIG. 18 is a schematic representation of RNA pentacistronic replicons, A526, A527, A554, A555 and A556, which encode five CMV proteins. Subgenomic promoters are shown by arrows, other control elements are marked.
[0046] FIG. 19 is a fluorescence histogram showing that BHKV cells transfected with the A527 RNA replicon express the gH / gL / UL128 / UL130 / UL131 complex. Cell staining was performed using antibodies that bind to a conformational epitope present in the pentameric complex (Macagno (2010) J. Virol. 84 (2): 1.005-13).
[0047] FIG. 20 is a schematic representation and a graph. The schematic representation shows replicons of bicistronic RNA, A160 and A531-A537, which encode CMV gH and gL. The graph shows neutralizing activity of immune sera from mice immunized with VRPs that contained the replicons.
[0048] FIG. 21 is a graph showing the anti-VZV protein antibody response in immune sera from mice immunized with monocistronic RNA replicons encoding VZV proteins or bicistronic RNA replicons encoding VZV gE and gI, or gH and gL. The mice were immunized with 7 g of RNA formulated with a CNE (see Example 7).
[0049] FIG. 22 is a graph showing anti-VZV protein antibody response in immune sera from mice immunized with monocistronic RNA replicons encoding VZV proteins or bicistronic RNA replicons encoding VZV gE and gI, or gH and gL. The mice were immunized with 1 μg of RNA formulated with a CNE (see Example 7). DETAILED DESCRIPTION OF THE INVENTION
[0050] The invention provides platforms for coliberation of herpesvirus proteins, for example, cytomegalovirus (CMV) proteins, to cells, particularly proteins that form complexes in vivo. In some modalities, these proteins and the complexes they form arouse potent neutralizing antibodies. The immune response produced by coliberation of herpesvirus proteins (for example, CMV), particularly those that form complexes in vivo (for example, gH / gL), may be superior to the immune response produced using other approaches. For example, an RNA molecule (for example, a replicon) that encodes both CMV gH and gL may induce better neutralizing titers and / or protective immunity compared to an RNA molecule that encodes gB, an RNA molecule that encodes gH , an RNA molecule that encodes gL, or even a mixture of RNA molecules that individually encode gH or gL. In addition, a replicon that encodes gH / gL / UL128 / UL130 / UL131 can provide superior responses over those that encode only gH / gL.
[0051] In a general aspect, the invention is related to the platforms for delivering two or more herpesvirus proteins (for example, CMV) to cells. The platforms comprise recombinant polycistronic nucleic acid molecules that contain a first sequence that encodes a first herpesvirus protein (eg, CMV) or fragment thereof, and a second sequence that encodes a second herpesvirus protein (eg, CMV) or fragment of this. If desired, one or more additional sequences encoding additional proteins, for example, a third herpesvirus protein (eg, CMV) or fragment thereof, a fourth herpesvirus protein (eg, CMV) or fragment thereof, a fifth protein herpesvirus (e.g. CMV) or fragment thereof etc. may be present in the recombinant polycistronic nucleic acid molecule. The sequences encoding herpesvirus proteins (eg, CMV) or fragments thereof are operationally linked to one or more suitable control elements so that herpesvirus proteins (eg, CMV) or fragments are produced by a cell containing the recombinant polycistronic nucleic acid.
[0052] In the polycistronic nucleic acids described herein, the first and second encoded herpesvirus proteins, or fragments thereof, and the third, fourth and fifth encoded herpesvirus proteins, or fragments thereof, if present, generally and preferably are of the same herpesvirus. In certain examples, all herpesvirus proteins, or fragments thereof, encoded by a polycistronic vector are CMV proteins or VZV proteins.
[0053] The recombinant polycistronic nucleic acid molecules described here provide the advantage of releasing sequences that encode two or more herpesvirus proteins (eg, CMV) to a cell, and direct the expression of herpesvirus proteins (eg, CMV) at levels sufficient to result in the formation of a protein complex containing the two or more herpesvirus proteins (eg, CMV) in vivo. Using this approach, the two or more encoded herpesvirus proteins (eg, CMV) can be expressed at sufficient intracellular levels for the formation of herpesvirus protein complexes (eg, CMV) (eg, gH / gL) . For example, encoded herpesvirus proteins (eg, CMV), or fragments thereof, can be expressed at substantially the same level or, if desired, at different levels by selecting appropriate expression control sequences (eg, promoters, IRES , site 2A, etc.). This is significantly the most efficient way to produce protein complexes in vivo than by coliberation of two or more individual DNA molecules that encode different herpesviruses (for example, CMV) to the same cell, which can be inefficient and highly variable. See, for example, WO 2004/076645.
[0054] The recombinant polycistronic nucleic acid molecule can be based on any desired nucleic acid such as, for example, DNA (for example, plasmid or viral DNA) or RNA. Any suitable DNA or RNA can be used as the nucleic acid vector that carries the open reading frames encoding herpesvirus proteins (eg, CMV) or fragments thereof. Suitable nucleic acid vectors have the ability to carry and direct the expression of more than one protein gene. Such nucleic acid vectors are known in the art and include, for example, plasmids, DNA obtained from DNA viruses such as vaccinia virus vectors (for example, NYVAC, see US 5,494,807) and poxvirus vectors ( for example, canarypox virus vector ALVAC, Sanofi Pasteur), and RNA obtained from suitable RNA viruses such as an alphavirus. If desired, the recombinant polycistronic nucleic acid molecule can be modified, for example, contain modified nucleobases and / or bonds, as described hereinafter. Preferably, the polycistronic nucleic acid molecule is an RNA molecule.
[0055] In some respects, the recombinant polycistronic nucleic acid molecule is a DNA molecule such as plasmid DNA. These DNA molecules can encode, for example, a polycistronic replicon and contain a mammalian promoter that directs transcription of the replicon. Recombinant or similar polycistronic nucleic acid molecules can be administered to a mammal and then transcribed in situ to produce a polycistronic replicon that expresses herpesvirus proteins.
[0056] In some ways, the invention is a polycistronic nucleic acid molecule that contains a sequence encoding a herpesvirus gH or fragment thereof, and a herpesvirus gL or a fragment thereof. The gH and gL proteins, or fragments thereof, can be of any desired herpesvirus such as, for example, HSV-1, HSV-2, VZV, EBV type 1, EBV type 2, CMV, HHV-6 type A, HHV-6 type B, HHV-7, KSHV, and the like. Preferably, the herpesvirus is VZV, HSV-2, HSV-1, EBV (type 1 or type 2) or CMV. Most preferably, the herpes virus is VZV, HSV-2 or CMV. Even more preferably, the herpesvirus is CMV. The sequences of gH and gL proteins and nucleic acids that encode the proteins of these viruses are well known in the art. Exemplary sequences are identified in Table 1. The polycistronic nucleic acid molecule can contain a first sequence that encodes a gH protein disclosed in the Table 1, or a fragment thereof, or a sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%), 98% or 99% identical to it. The polycistronic acid nucleic acid molecule can also contain a second sequence that encodes a gL protein disclosed in Table 1, or a fragment thereof, or a sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to it.Table 1

[0057] In this description of the invention, to facilitate a clear description of nucleic acids, particular components of the sequence are called a "first sequence", a "second sequence" etc. It must be understood that the first and second strings can appear in any order or orientation desired, and that one does not want to define a particular order or orientation by the words "first", "second" etc. Similarly, protein complexes are cited by listing the proteins that are present in the complex, for example, gH / gL. This aims to describe the complex by the proteins that are present in the complex, and does not indicate relative amounts of the proteins or the order or orientation of sequences that encode the proteins in a recombinant nucleic acid.
[0058] Certain preferred embodiments, for example, VRP and alphavirus self-replicating RNA containing sequences encoding CMV proteins, are further described herein. It is intended that the sequences that encode CMV proteins in these preferred modalities can be replaced with sequences that encode proteins, for example, gH and gL, from other herpesviruses. Alphavirus VRP platforms
[0059] In some embodiments, CMV proteins are released to a cell using alphavirus replicon (VRP) particles that employ polycistronic replicons (or vectors) as described below. As used herein, the term “polycistronic” includes bicistronic vectors, as well as vectors that comprise three or more citrons. Citrons in a polycistronic vector can encode CMV proteins from the same or different CMV strains. Citrons can be oriented in any 5'-3 'order. Any sequence of nucleotides that encodes a CMV protein can be used to produce the protein. Exemplary sequences useful for preparing polycistronic nucleic acids that encode two or more CMV proteins or fragments thereof are described herein.
[0060] As used herein, the term “alphavirus” has its conventional meaning in the art and includes several species such as, for example, Venezuelan equine encephalitis virus (VEE; for example, Trinidad donkey, TC83CR etc.), Semliki Forest virus (SFV), Sindbis virus, Ross river virus, western equine encephalitis virus, eastern equine encephalitis virus, Chikungunya virus, SA AR86 virus, Everglades virus, Mucambo virus, Barmah Forest virus, Middelburg virus, Pixuna virus, O 'virus nyong-nyong, Getah virus, Sagiyama virus, Bebaru virus, Mayaro virus, Una virus, Aura virus, Whataroa virus, Banbanki virus, Kyzylagach virus, Highlands J. virus, Fort Morgan virus, Ndumu virus and Buggy Creek virus. The term "alphavirus" can also include chimeric alphaviruses (for example, as described by Perri et al., (2003) J. Virol. 77 (19): 10.394-403) that contain sequences from the genome of more than one alphavirus.
[0061] An "alphavirus replicon particle" (VRP) or "replicon particle" is an alphavirus replicon packaged with structural alphavirus proteins.
[0062] An "alphavirus replicon" (or "replicon") is an RNA molecule that can direct its own amplification in vivo in a target cell. The replicon encodes the polymerase (s) that catalyzes RNA amplification (nsP1, nsP2, nsP3, nsP4) and contains cis RNA sequences necessary for replication that are recognized and used by the encoded polymerase (s) ( s). An alphavirus replicon typically contains the following ordered elements: 5 'viral sequences needed in cis for replication, sequences encoding non-structural biologically active alphavirus proteins (nsP1, nsP2, nsP3, nsP4), 3' viral sequences needed in cis for replication , and a trace of polyadenylate. An alphavirus replicon can also contain one or more viral subgenomic promoters from the "junction region" that direct the expression of heterologous nucleotide sequences, which can, in certain embodiments, be modified to increase or reduce the viral transcription of the subgenomic fragment and the heterologous sequence (s) to be expressed. Other control elements can be used, as described below.
[0063] Replicons of alphaviruses encoding CMV proteins are used to produce VRPs. These alphavirus replicons comprise sequences that encode at least two CMV proteins or fragments thereof. These sequences are operationally linked to one or more suitable control elements, for example, a subgenomic promoter, an IRES (for example, EMCV, EV71) and a viral 2A site, which can be the same or different. The release of components from these complexes using the polycistronic vectors disclosed here is an efficient way to provide sequences of nucleic acids that encode two or more CMV proteins in desired relative quantities; whereas if multiple alphavirus constructs are used to release individual CMV proteins for complex formation, efficient VRP coliberation would be necessary.
[0064] Any combination of suitable control elements can be used in any order. In one example, a single subgenomic promoter is operationally linked to two sequences that encode two different CMV proteins, and an IRES is positioned between the two coding sequences. In another example, two sequences that encode two different CMV proteins are operationally linked to separate promoters. In yet another example, the two sequences that encode two different CMV proteins are operationally linked to a single promoter. The two sequences that encode two different CMV proteins are linked together by means of a nucleotide sequence that encodes a viral 2A site and thus encode a single chain of amino acids that contain the amino acid sequences of both CMV proteins . The viral 2A site in this context is used to generate two CMV proteins from the encoded polyprotein. Subgenomic promoters
[0065] Subgenomic promoters, also known as junction region promoters, can be used to regulate protein expression. Alpha-viral subgenomic promoters regulate the expression of alpha-viral structural proteins. See Strauss and Strauss, “The Alfaviruses: Gene Expression, Replication, and Evolution”, Microbiol. Rev. September 1994; 58 (3): 491-562. A polycistronic polynucleotide can comprise a subgenomic promoter of any alphavirus. When two or more subgenomic promoters are present in a polycistronic polynucleotide, the promoters can be the same or different. For example, the subgenomic promoter may have the sequence CTCTCTACGGCTAACCTGAATGGA (SEQ ID. NO: 1). In certain embodiments, subgenomic promoters can be modified in order to increase or reduce the viral transcription of proteins. See U.S. Patent No. 6,592,874. Internal ribosome entry site (IRES)
[0066] In some modalities, one or more control elements are an internal ribosome entry site (IRES). An IRES allows multiple proteins to be made from a single mRNA transcript, as ribosomes bind to each IRES and initiate translation in the absence of a 5'-cap, which is normally necessary to initiate protein translation in eukaryotic cells. For example, the IRES can be EV71 or EMCV. Viral 2A site
[0067] The FMDV 2A protein is a short peptide that serves to separate the structural proteins of FMDV from a non-structural protein (FMDV 2B). An initial study on this peptide suggested that it acts as an autocatalytic protease, but other work (eg, Donnelly et al., (2001), J. Gen. Virol. 82,1.013-1.025) suggests that this short sequence and the only next FMDV 2B amino acid (Gly) acts as a stop-start for translation. Regardless of the precise mode of action, the sequence can be inserted between two polypeptides, and produce multiple individual polypeptides from a single open reading frame. In the context of this invention, FMDV 2A sequences can be inserted between sequences that encode at least two CMV proteins, allowing their synthesis as part of a single open reading frame. For example, the open reading frame can encode a gH protein and a gL protein separated by a sequence that encodes a viral 2A site. Then a single mRNA is transcribed during the translation stage, the gH and gL peptides are produced separately as a function of the activity of the viral 2A site. Any suitable viral 2A sequence can be used. Often, a viral 2A site comprises the consensus sequence Asp-Val / Ile-Glu-X-Asn-Pro-Gly-Pro, where X is any amino acid (SEQ ID. NO: 2). For example, the 2A peptide sequence of foot-and-mouth disease virus 2 is DVESNPGP (SEQ ID. NO: 3). See Trichas et al., “Use of the viral 2A peptide for bicistronic expression in transgenic mice”, BMC Biol. September 15, 2008; 6: 40, and Halpin et al., “Self-processing 2A-polyproteins - a system for coordinate expression of multiple proteins in transgenic plants”, Plant J. February 1999; 17 (4): 453-9.
[0068] In some embodiments, an alphavirus replicon is a chimeric replicon, for example, a VEE-Sindbis chimeric replicon (VCR) or a VEE-strain TC83 (TC83R) replicon or a TC83-Sindbis chimeric replicon (TC83CR ). In some embodiments, a VCR contains the packaging signal and RTU 3 'of a Sindbis replicon in place of sequences in nsP3 and at the 3' end of the VEE replicon; see Perri et al, J. Virol. 77,10.394-403,2003. In some embodiments, a TC83CR contains the packaging signal eUTR 3'de a replicon Sindbis in place of sequences in nsP3 and at the end3'of a VEE TC83 replicon duplicate. Production of VRPs
[0069] Methods of preparing VRPs are well known in the art. In some embodiments, an alphavirus is mounted on a VRP using a packaging cell. An “alphavirus packaging cell” (or “packaging cell”) is a cell that contains one or more alphavirus structural protein expression cassettes and that produces recombinant alphavirus particles after introducing an alphavirus replicon, initiation system stratified eukaryotic vector (for example, US Patent 5,814,482) or recombinant alphavirus particle. The (one or more) different alphavirus structural protein cassettes serve as "helpers" by supplying the alphavirus structural proteins. An "alphavirus structural protein cassette" is an expression cassette that encodes one or more alphavirus structural proteins and comprises at least one and up to five copies (that is, 1, 2, 3, 4 or 5) of a sequence of recognition of alphavirus replicase. Structural protein expression cassettes typically comprise, from 5 'to 3', a 5 'sequence that initiates alphavirus RNA transcription, a promoter from the optional alphavirus subgenomic region, a nucleotide sequence that encodes the alphavirus structural protein, a 3 'untranslated region (which also directs RNA transcription) and a polyA trace. See, for example, WO 2010/019437.
[0070] In preferred embodiments, two different alphavirus structural protein cassettes (split defective helpers) are used in a packaging cell to minimize the recombination events that could produce a replication-competent virus. In some embodiments, an alphavirus structural protein cassette encodes the capsid protein (C), but none of the glycoproteins (E2 and E1). In some embodiments, an alphavirus structural protein cassette encodes the capsid protein and the E1 or E2 glycoproteins (but not both). In some embodiments, an alphavirus structural protein cassette encodes glycoproteins E2 and E1, but not the capsid protein. In some embodiments, an alphavirus structural protein cassette encodes the glycoprotein E1 or E2 (but not both) and not the capsid protein.
[0071] In some modalities, VRPs are produced by the simultaneous introduction of replicons and RNAs helpers in cells from various sources. Under these conditions, for example, BHKV cells (1 x 107) are electroporated to, for example, 220 volts, 1,000 μF, 2 pulses manually with 10 μg of replicon RNA: 6 μg of defective Cap helper RNA: 10 μg of Defective Gly helper RNA, and the alphavirus-containing supernatant is collected approximately 24 hours later. Replicons and / or helpers can also be introduced in forms of DNA that launch suitable RNAs into transfected cells.
[0072] A packaging cell can be a mammalian cell or a non-mammalian cell, for example, an insect cell (for example, SF9) or avian (for example, a primary chick or duck fibroblast or fibroblast cell line ). See U.S. Patent 7,445,924. Sources of avian cells include, without limitation, avian embryonic stem cells such as, for example, EB66® (VIVALIS); chicken cells, including chicken embryonic stem cells such as EBx® cells, chicken embryonic fibroblasts and chicken embryonic germ cells; duck cells such as, for example, the cell lines AGE1.CR and AGE1.CR.pIX (ProBioGen) which are described, for example, in Vaccine 27: 4.975-4.982 (2009) and WO 2005/042728); and goose cells. In some embodiments, a packaging cell is a primary duck fibroblast or lineage of duck retinal cells, for example, AGE.CR (PROBIOGEN).
[0073] Sources of mammalian cells for simultaneous introduction of nucleic acid and / or packaging cells include, without limitation, human or non-human primate cells, including PerC6 (PER.C6) cells (CRUCELL NV), which are described by for example, in WO 01/38362 and WO 02/40665, in addition to those deposited under deposit number ECACC 96022940); MRC-5 (ATCC CCL-171); WI-38 (ATCC CCL-75); fetal lung cells rhesus (ATCC CL-160); human embryonic kidney cells (for example, 293 cells, typically transformed by type 5 adenovirus trimmed DNA); monkey kidney VERO cells); horse, cow (eg MDBK cells), sheep, dog cells (eg dog kidney MDCK cells, ATCC CCL34 MDCK (NBL2) or MDCK 33016, DSM deposit number ACC 2219, as described in WO 97/37001); cat, and rodent cells (e.g., hamster cells such as BHK21-F, HKCC cells, or Chinese hamster ovary (CHO) cells), and can be obtained from a wide variety of stages of development including , for example, adults, neonates, fetuses and embryos.
[0074] In some modalities, a packaging cell is stably transformed with one or more structural protein expression cassettes. Structural protein expression cassettes can be introduced into cells using standard recombinant DNA techniques, including transferrin-mediated DNA transfer, polycation, naked or encapsulated nucleic acid transfection, liposome-mediated cell fusion, intracellular transport of coated latex globules with DNA, protoplast fusion, viral infection, electroporation, “gene gun” methods and transfection mediated by DEAE or calcium phosphate. Structural protein expression cassettes are typically introduced into a host cell as DNA molecules, but can also be introduced as RNA transcribed in vitro. Each expression cassette can be inserted separately or substantially simultaneously.
[0075] In some embodiments, stable alphavirus packaging cell lines are used to produce recombinant alphavirus particles. These are alpha-virus-permissive cells that comprise DNA cassettes that express the defective helper RNA stably integrated into their genomes. See Polo et al, Proc. Natl. Acad. Sci. U.S.A. 96, 4.598-603, 1999. Helper RNAs are constitutively expressed, but alphavirus structural proteins are not, since the genes are under the control of a subgenomic alphavirus promoter (Polo et al., 1999). After introducing an alphavirus replicon into the genome of a packaging cell by transfection or VRP infection, replicase enzymes are produced that trigger the expression of the capsid and glycoprotein genes in helper RNAs, and outbound VRPs are produced. The introduction of the replicon can be achieved by several methods, including both transfection and infection with a seed stock of alphavirus replicon particles. The packaging cell is then incubated under conditions and for a sufficient time to produce alphavirus replicon particles packaged in the culture supernatant.
[0076] In this way, the packaging cells allow VRPs to act as self-propagating viruses. This technology allows VRPs to be produced in basically the same way and using the same equipment as that used for live attenuated vaccines or other viral vectors that have producer cell lines available, for example, replication-incompetent adenovirus vectors developed in cells that express the adenovirus E1A and E1B genes.
[0077] In some embodiments, a two-step process is used: the first step comprises the production of a seed seeding stock of alphavirus replicon particles by transfecting a packaging cell with a replicon RNA or DNA-based replicon plasmid. A much larger stock of replicon particles is then produced in a second step, by infecting a fresh culture of packaging cells with the seeding stock. This infection can be performed using multiple multiplicities of infection (MOI), including an MOI = 0.00001, 0.00005, 0.0001, 0.0005, 0.001, 0.005, 0.01, 0.05, 0.1, 0.5, 1.0, 3, 5, 10 or 20. In some modalities, the infection is carried out at a low MOI (for example, less than 1). Over time, replicon particles can be collected from packaging cells infected with the seeding stock. In some embodiments, replicon particles can then be passed into even larger cultures of virgin packaging cells by repeated low multiplicity infection, resulting in commercial scale preparations with the same high titration. Self-replicating RNA platforms
[0078] Two or more CMV proteins can be produced by expression of recombinant nucleic acids that encode proteins in an individual's cells. Preferably, the recombinant nucleic acid molecules encode two or more CMV proteins, for example, are polycistronic. As defined above, “polycistronic” includes bicistronic. Preferred nucleic acids that can be administered to an individual to cause the production of CMV proteins are self-replicating RNA molecules. The self-replicating RNA molecules of the invention are based on the genomic RNA of RNA viruses, but lack the genes that encode one or more structural proteins. The self-replicating RNA molecules are capable of being translated to produce non-structural proteins of the RNA virus and CMV proteins encoded by the self-replicating RNA.
[0079] The self-replicating RNA generally contains at least one or more genes selected from the group consisting of viral replicase, viral proteases, viral helicases and other non-structural viral proteins, and also comprises 5 'and 3' end replication sequences cis-active, and a heterologous sequence that encodes two or more desired CMV proteins. A subgenomic promoter that directs the expression of the heterologous sequence (s) can be included in the self-replicating RNA. If desired, a heterologous sequence can be fused in frame to other coding regions in the self-replicating RNA and / or can be under the control of an internal ribosome entry site (IRES).
The self-replicating RNA molecules of the invention can be designed in such a way that the self-replicating RNA molecule cannot induce the production of infectious viral particles. This can be achieved, for example, by omitting one or more viral genes that encode structural proteins that are necessary for the production of viral particles in the self-replicating RNA. For example, when the self-replicating RNA molecule is based on an alphavirus, for example, on the Sindbis virus (SIN), Semliki Forest virus and Venezuelan equine encephalitis virus (VEE), one or more genes that encode structural viral proteins, for example, capsid and / or envelope glycoproteins can be omitted. If desired, the self-replicating RNA molecules of the invention can be designed to induce the production of infectious viral particles that are attenuated or virulent, or to produce viral particles that are capable of a single round of subsequent infection.
[0081] A self-replicating RNA molecule can, when released to a vertebrate cell, even without any protein, lead to the production of multiple child RNAs by transcribing itself (or an antisense copy of itself). The self-replicating RNA can be translated directly after release to a cell, and that translation provides an RNA-dependent RNA polymerase which then produces transcripts of the released RNA. In this way, the released RNA leads to the production of multiple child RNAs. These transcripts are antisense to the released RNA and can themselves be translated to provide in situ expression of the encoded CMV protein, or they can be transcribed to provide additional transcripts with the same sense as the released RNA and then translated to provide in situ expression of the encoded CMV protein (s).
[0082] A suitable system for obtaining self-replication is the use of an alphavirus-based RNA replicon, for example, an alphavirus replicon as described herein. These tape + replicons are translated after release to a cell to produce a replicase (or replicase-transcriptase). The replicase is translated as a polyprotein that self-cleaves to provide a replication complex that creates genomic copies of strand - of the released + stranded RNA. These tape strips themselves - can be transcribed to generate additional copies of the strand + parent RNA and also to give rise to one or more subgenomic transcripts encoding two or more CMV proteins. The translation of the subgenomic transcript thus leads to the in situ expression of the CMV protein (s) by the infected cell. Suitable replicas of alphaviruses can use a replicase of a Sindbis virus, a Semliki Forest virus, an Eastern equine encephalitis virus, a Venezuelan equine encephalitis virus, etc.
[0083] Thus, a preferred self-replicating RNA molecule encodes: (i) an RNA-dependent RNA polymerase that can transcribe RNA from the self-replicating RNA molecule and (ii) two or more CMV proteins or fragments thereof. The polymerase can be an alphavirus replicase, for example, which comprises the alphavirus protein nsP4. The nsP4 protein is the crucial catalytic component of replicase.
[0084] While the natural alphavirus genomes encode structural virion proteins in addition to the non-structural replicase polyprotein, it is preferred that an alphavirus-based self-replicating RNA molecule of the invention does not encode all alphavirus structural proteins. Thus, self-replicating RNA can lead to the production of genomic RNA copies of itself in a cell, but not to the production of alphavirus virions that contain RNA. The inability to produce these virions means that, unlike a wild-type alphavirus, the self-replicating RNA molecule cannot be perpetuated in an infectious form. The structural proteins of alphaviruses that are necessary for perpetuation in wild-type viruses are absent from self-replicating RNAs of the invention and their place is occupied by the gene (s) that encode the desired gene product (CMV protein or fragment thereof), of such that the subgenomic transcript encodes the desired gene product instead of the structural proteins of the alphavirus virion.
[0085] Thus, a self-replicating RNA molecule useful with the invention has two sequences that encode different CMV proteins or fragments thereof. The sequences encoding the CMV proteins or fragments can be in any desired orientation, and can be operationally linked to the same or separate promoters. If desired, the sequences encoding CMV proteins or fragments can be part of a single open reading frame. In some embodiments, the RNA may have one or more additional downstream sequences or frames, for example, that encode other additional CMV proteins or fragments thereof. A self-replicating RNA molecule can have a 5 'sequence that is compatible with the encoded replicase.
[0086] In one aspect, the self-replicating RNA molecule is derived from or based on an alphavirus, for example, an alphavirus replicon, as defined herein. In other respects, the self-replicating RNA molecule is derived from or based on a virus other than an alphavirus, preferably a positive RNA virus and, more preferably, a picornavirus, flavivirus, rubivirus, pestivirus, hepacivirus, calicivirus or coronavirus. Suitable wild-type alphavirus sequences are well known and are available through sequence depositories, for example, the "American Type Culture Collection", Rockville, Md. Representative examples of suitable alphaviruses include the Aura virus (ATCC VR-368), viruses Bebaru (ATCC VR-600, ATCC VR-1240), Cabassou (ATCC VR-922), Chikungunya virus (ATCC VR-64, ATCC VR-1241), Eastern Equine Encephalomyelitis Virus (ATCC VR-65, ATCC VR-1242 ), Fort Morgan (ATCC VR-924), Getah virus (ATCC VR-369, ATCC VR-1243), Kyzylagach (ATCC VR-927), Mayaro virus (ATCCVR-66; ATCC VR-1277), Middleburg (ATCC VR -370), Mucambo virus (ATCC VR-580, ATCC VR-1244), Ndumu (ATCC VR-371), Pinuna virus (ATCC VR-372, ATCC VR-1245), Ross river virus (ATCC VR-373, ATCC VR-1246), Semliki Forest (ATCC VR-67, ATCC VR-1247), Sindbis virus (ATCC VR-68, ATCC VR-1248), Tonate (ATCC VR-925), Triniti (ATCC VR-469), Una (ATCC VR-374), Venezuelan equine encephalomyelitis (ATCC VR-69, ATCC VR-923, ATCC VR-1250 ATCC VR-12 49, ATCC VR-532), western equine encephalomyelitis (ATCC VR-70, ATCC VR-1251, ATCC VR-622, ATCC VR-1252), Whataroa (ATCC VR-926) and Y-62- 33 (ATCC VR- 375).
The self-replicating RNA molecules of the invention can contain one or more modified nucleotides and, therefore, have increased stability and are resistant to degradation and clearance in vivo, and other advantages. Without adhering to a specific theory, self-replicating RNA molecules that contain modified nucleotides are believed to prevent or reduce the stimulation of endosomal and cytoplasmic immune receptors when self-replicating RNA is released in a cell. This allows self-replication, amplification and protein expression to occur. This also reduces safety concerns regarding self-replicating RNA that does not contain modified nucleotides, as self-replicating RNA that contains modified nucleotides reduces activation of the innate immune system and subsequent unwanted consequences (eg, injection site inflammation) , irritation at the injection site, pain, and the like). It is also believed that RNA molecules produced as a result of self-replication are recognized as foreign nucleic acids by cytoplasmic immune receptors. Thus, self-replicating RNA molecules that contain modified nucleotides allow efficient amplification of RNA in a host cell and the expression of CMV proteins, as well as adjuvant effects.
[0088] The RNA sequence can be modified with respect to its use of codons, for example, to increase the efficiency of translation and the half-life of RNA. A poly A tail (for example, about 30 adenosine residues or more) can be attached to the 3 'end of the RNA to increase its half-life. The 5 'end of the RNA can be covered with a modified fibronucleotide with the m7G (5') ppp (5 ') N structure (cap 0 structure) or a derivative thereof, which can be incorporated during RNA synthesis or can be created enzymatically after RNA transcription (for example, by using the vaccinia virus covering enzyme (VCE) which consists of mRNA triphosphatase, guanylyl transferase and guanine-7-methyltransferase, which catalyzes the construction of 0N7-monomethylated cap structures). The cap 0 structure can provide stability and translation efficiency to the RNA molecule. The 5 'cap of the RNA molecule can also be modified by a 2'-O-Methyltransferase, which results in the generation of a cap 1 structure (m7Gppp [m2'-0] N), which can further increase efficiency of translation. A cap 1 structure can also increase potency in vivo.
[0089] As used herein, the term "modified nucleotide" refers to a nucleotide that contains one or more chemical modifications (for example, substitutions) within or on the nitrogenous bases of the nucleoside (for example, cytosine (C), thymine (T ) or uracil (U), adenine (A) or guanine (G)). If desired, a self-replicating RNA molecule may contain chemical modifications within or in the sugar portion of the nucleoside (for example, ribose, deoxyribose, modified ribose, modified deoxyribose, six-membered sugar analog or open chain sugar analog) , or phosphate.
The self-replicating RNA molecules may contain at least one modified nucleotide, which is preferably not part of cap 5 '(for example, in addition to the modification which is part of cap 5'). Consequently, the self-replicating RNA molecule may contain a modified nucleotide in a single position, it may contain a particular modified nucleotide (for example, pseudouridine, N6-methyladenosine, 5-methylcitidine, 5-methyluridine) in two or more positions, or it can contain two, three, four, five, six, seven, eight, nine, ten or more modified nucleotides (for example, each in one or more positions). Preferably, the self-replicating RNA molecules comprise modified nucleotides that contain a modification in or on the nitrogenous base, but do not contain modified sugar or phosphate moieties.
[0091] In some examples, between 0.001% and 99% or 100% of the nucleotides in a self-replicating RNA molecule are modified nucleotides. For example, 0.001% -25%, 0.01% - 25%, 0.1% -25% or 1% -25% of the nucleotides in a self-replicating RNA molecule are modified nucleotides.
[0092] In other examples, between 0.001% and 99% or 100% of a particular unmodified nucleotide in a self-replicating RNA molecule is replaced with a modified nucleotide. For example, about 1% of the nucleotides in the self-replicating RNA molecule that contain uridine can be modified, for example, by replacing uridine with pseudouridine. In other examples, the desired amount (percentage) of two, three or four particular nucleotides (nucleotides that contain uridine, cytidine, guanosine or adenine) in a self-replicating RNA molecule are modified nucleotides. For example, 0.001% -25%, 0.01% -25%, 0.1% -25 or 1% -25% of a particular nucleotide in a self-replicating RNA molecule are modified nucleotides. In other examples, 0.001% -20%, 0.001% -15%, 0.001% -10%, 0.01% -20%, 0.01% -15%, 0.1% -25, 0.01% - 10%, 1% -20%, 1% -15%, 1% -10% or about 5%, about 10%, about 15%, about 20% of a particular nucleotide in an auto RNA molecule -replicants are modified nucleotides.
[0093] It is preferred that less than 100% of the nucleotides in a self-replicating RNA molecule are modified nucleotides. It is also preferred that less than 100% of a particular nucleotide in a self-replicating RNA molecule is modified nucleotides. Accordingly, preferred self-replicating RNA molecules comprise at least some unmodified nucleotides.
[0094] There are more than 96 naturally occurring nucleoside modifications found in mammalian RNA. See, for example, Limbach et al., Nucleic Acids Research, 22 (12): 2,183-2,196 (1994). The preparation of nucleotides and modified nucleotides and nucleosides is well known in the art, for example, by US Patent Numbers 4373071, 4458066, 4500707, 4668777, 4973679, 5047524, 5132418, 5153319, 5262530, 5700642 all of which are incorporated herein by reference in their entirety, and many modified nucleosides and modified nucleotides are commercially available.
[0095] Modified nucleobases that can be incorporated into modified nucleosides and nucleotides and be present in RNA molecules include: m5C (5-methylcytidine), m5U (5-methyluridine), m6A (N6-methyladenosine), s2U (2-thiouridine) , One (2'-O-methyluridine), m1A (1-methyladenosine); m2A (2-methyladenosine); Am (2-1-O-methyladenosine); ms2m6A (2-methylthio-N6-methyladenosine); i6A (N6-isopentenyladenosine); ms2i6A (2-methylthio-N6isopentenyladenosine); io6A (N6- (cis-hydroxyisopentenyl) adenosine); ms2io6A (2-methylthio-N6- (cis-hydroxyisopentenyl) adenosine); g6A (N6-glycinylcarbamoyladenosine); t6A (N6-threonyl carbamoyladenosine); ms2t6A (2-methylthio-N6-threonyl carbamoyladine) (m6 -6); m6 - threonylcarbamoyladenosine); hn6A (N6-hydroxynorvalylcarbamoyladenosine); ms2hn6A (2-methylthio-N6-hydroxinorvalylcarbamoyladenosine); Ar (p) (2'-O-ribosyladenosine (phosphate)); I (inosine); m1I (1-methylinosine); m'Im (1,2'-O-dimethylinosine); m3C (3-methylcytidine); Cm (2T-O-methylcytidine); s2C (2-thiocytidine); ac4C (N4-acetylcytidine); f5C (5-formylcytidine); m5Cm (5,2-O-dimethylcytidine); ac4Cm (N4-acetyl-2TO-methylcytidine); k2C (lysidine); m1G (1-methylguanosine); m2G (N2-methylguanosine); m7G (7-methylguanosine); Gm (2'-O-methylguanosine); m22G (N2, N2-dimethylguanosine); m2Gm (N2,2'-O-dimethylguanosine); m22Gm (N2, N2,2'-O-trimethylguanosine); Gr (p) (2'-O-ribosylguanosine (phosphate)); yW (wibutosine); o2yW (peroxiwibutosine); OHyW (hydroxywibutosine); OHyW * (non-hydroxywibutosine) modified); imG (wiosin); mimG (methylguanosine); Q (queuosin); oQ (epoxyqueuosine); galQ (galatactosyl-queuosin); manQ (mannosyl-queuosine); price (7-cyano-7-deazaguanosine); price (7-aminomethyl-7-deazaguanosine); G * (arcaeosine); D (dihydrouridine); m5Um (5,2'-O-dimethyluridine); s4U (4-thiouridine); m5s2U (5-methyl-2-thiouridine); s2Um (2-thio-2'-O-methyluridine); acp3U (3- (3-amino-3-carboxypropyl) uridine); ho5U (5-hydroxyuridine); mo5U (5-methoxyuridine); cmo5U (uridine 5-oxyacetic acid); mcmo5U (5-oxyacetic acid uridine methyl ester); chm5U (5- (carboxyhydroxymethyl) uridine)); mchm5U (5- (carboxyhydroxymethyl) uridine methyl ester); mcm5U (5-methoxycarbonylmethyluridine); mcm5Um (S-methoxycarbonylmethyl-2-O-methyluridine); mcm5s2U (5-methoxycarbonylmethyl-2-thiouridine); nm5s2U (5-aminomethyl-2-thiouridine); mnm5U (5-methylaminomethyluridine); mnm5s2U (5-methylaminomethyl-2-thiouridine); mnm5se2U (5-methylaminomethyl-2-selenouridine); ncm5U (5-carbamoylmethyluridine); ncm5Um (5-carbamoylmethyl-2'-O-methyluridine); cmnm5U (5-carboxymethylaminomethyluridine); cnmm5Um (5-carboxymethyl aminomethyl-2-L-O-ethyluridine); cmnm5s2U (5-carboxymethylaminomethyl-2-thiouridine); m62A (N6, N6-dimethyladenosine); Tm (2'-O-methylinosine); m4C (N4-methylcytidine); m4Cm (N4,2-O-dimethylcytidine); hm5C (5-hydroxymethylcitidine); m3U (3-methyluridine); cm5U (5-carboxymethyluridine); m6Am (N6, T-O-dimethyladenosine); rn62Am (N6, N6, O-2-trimethyladenosine); ni27G (N2,7-dimethylguanosine); m2'27G (N2, N2,7-trimethylguanosine); m3Um (3,2T-O-dimethyluridine); m5D (5-methyldihydrouridine); f5Cm (5-formyl-2'-O-methylcytidine); m1Gm (1,2'-O-dimethylguanosine); m'Am (1,2-O-dimethyladenosine) irinomethyluridine); tm5s2U (S-taurinomethyl-2-thiouridine) )); imG-14 (4-demethylguanosine); imG2 (isoguanosine); ac6A (N6-acetyladenosine), hypoxanthine, inosine, 8-oxo-adenine, 7-substituted derivatives thereof, dihydrouracil, pseudouracil, 2-thiouracil, 4-thiouracil, 5-aminouracil, 5- (C1-C6) - alkyluracil, 5-methyluracil, 5- (C2-C6) -alkenyluracil, 5- (C2-C6) -alquinyluracil, 5- (hydroxymethyl) uracil, 5-chlorouracil, 5-fluorouracil, 5-bromouracil, 5-hydroxycytosine, 5- (C1-C6) -alkylcytosine, 5-methylcytosine, 5- (C2-C6) -alkenylcytosine, 5- (C2-C6) -alkynylcytosine, 5-chlorocytosine, 5-fluorocytosine, 5-bromocytosine, N2-dimethylguanine, 7-deazaguanine, 8-azaguanine, guanine 7-deaza-7-substituted, 7-deaza-7- (C2-C6) alkynylguanine, guanine7-deaza-8-substituted, 8-hydroxyguanine, 6-thioguanine, 8-oxoguanine, 2-aminopurine, 2-amino-6-chloropurine, 2,4-diaminopurine, 2,6-diaminopurine, 8-azapurine, substituted 7-deazapurine, substituted 7-deaza-7-purine, purine7-deaza-8-substituted, hydrogen (abasic residue), m5C, m5U, m6A, s2U, W or 2'-O-methyl-U. Any or any combination of these modified nucleobases can be included in the self-replicating RNA of the invention. Many of these modified nucleobases and their corresponding ribonucleosides are available from commercial suppliers.
[0096] If desired, the self-replicating RNA molecule may contain phosphoramidate, phosphorothioate and / or methylphosphonate bonds.
[0097] Self-replicating RNA molecules that comprise at least one modified nucleotide can be prepared using any suitable method. Several suitable methods are known in the art for the production of RNA molecules that contain modified nucleotides. For example, a self-replicating RNA molecule that contains modified nucleotides can be prepared by transcribing (for example, in vitro transcription) a DNA encoding the self-replicating RNA molecule using a suitable DNA-dependent RNA polymerase, for example, T7 phage RNA polymerase, SP6 phage RNA polymerase, T3 phage RNA polymerase, and the like, or mutants of these polymerases that allow efficient incorporation of modified nucleotides into RNA molecules. The transcription reaction will contain modified nucleotides and nucleotides, and other components that support the selected polymerase activity, such as, for example, a suitable buffer, and suitable salts. The incorporation of nucleotide analogs into a self-replicating RNA can be planned, for example, to alter the stability of these RNA molecules, to increase resistance against RNAses, to establish replication after introduction into suitable host cells (RNA “infectivity”) ) and / or to induce or reduce innate and adaptive immune responses.
[0098] Suitable synthetic methods can be used alone, or in combination with one or more other methods (for example, recombinant DNA or RNA technology), to produce a self-replicating RNA molecule that contains one or more modified nucleotides. Suitable methods for de novo synthesis are well known in the art and can be adapted for particular applications. Exemplary methods include, for example, chemical synthesis using suitable protecting groups such as, for example, EMF (Masuda et al., (2007) Nucleic Acids Symposium Series 57: 3-4), the β-cyanoethyl phosphoramidite method (Beaucage SL et al (1981) Tetrahedron Lett. 22: 1,859); the nucleoside H-phosphonate method (Garegg P. et al (1986) Tetrahedron Lett. 27: 4.051-4; Froehler BC et al (1986) Nucl Acid Res. 14: 5.399-407; Garegg P. et al. (1986) Tetrahedron Lett. 27: 4.055-8; Gaffney BL et al (1988) Tetrahedron Lett. 29: 2.619 22). These chemicals can be performed or adapted for use with commercially available automated nucleic acid synthesizers. Additional suitable synthetic methods are disclosed in Uhlmann et al. (1990) Chem. Rev. 90: 544-84, and Goodchild J. (1990) Bioconjugate Chem. 1: 165. Nucleic acid synthesis can also be performed using recombinant methods that are well known and conventional in the art, including cloning, processing and / or expression of polynucleotides and gene products encoded by these polynucleotides. DNA shuffling by random fragmentation and reassembly by PCR of gene fragments and synthetic polynucleotides are examples of known techniques that can be used for the design and planning of polynucleotide sequences. Site-directed mutagenesis can be used to alter nucleic acids and encoded proteins, for example, to insert new restriction sites, alter glycosylation patterns, alter codon preference, produce splice variants, introduce mutations and the like. Suitable methods for transcription, translation and expression of nucleic acid sequences are known and conventional in the art (see generally, "Current Protocols in Molecular Biology", Vol. 2, Ed. Ausubel, et al., Greene Publish. Assoc. And Wiley Interscience, Chapter 13.1988; Glover, "DNA Cloning", Vol. II, IRL Press, Wash., DC, Chapter 3.1986; Bitter, et al., In Methods in Enzymology 153: 516-544 (1987); "The Molecular Biology of the Yeast Saccharomyces", Eds. Strathern et al., Cold Spring Harbor Press, Vol. I and II, 1982; and Sambrook et al., "Molecular Cloning: A Laboratory Manual", Cold Spring Harbor Press, 1989).
[0099] The presence and / or amount of one or more modified nucleotides in a self-replicating RNA molecule can be determined using any suitable method. For example, a self-replicating RNA can be digested into monophosphates (for example, using P1 nuclease) and dephosphorylated (for example, using a suitable phosphatase, for example, CIAP), and the resulting nucleosides analyzed by reverse phase HPLC (by example, using a YMC Pack ODS-AQ column (5 microns, 4.6 X 250 mm) and eluted using a gradient of 30% B (0-5 min) to 100% B (5-13 min) and the 100% B (13-40) min, flow rate (0.7 ml / min), UV detection (wavelength: 260 nm), column temperature (30 ° C), Buffer A (20 mM acid acetic - ammonium acetate pH 3.5), buffer B (20 mM acetic acid - ammonium acetate pH 3.5 / methanol [90/10])).
[0100] The self-replicating RNA can be associated with a delivery system. The self-replicating RNA can be administered with or without an adjuvant. RNA release systems
[0101] The self-replicating RNAs described here are suitable for release in several modalities, for example, release of naked RNA or in combination with lipids, polymers or other compounds that facilitate entry into cells. The self-replicating RNA molecules can be introduced into target cells or individuals using any suitable technique, for example, by direct injection, microinjection, electroporation, lipofection, biolistics, and the like. The self-replicating RNA molecule can also be introduced into cells via receptor-mediated endocytosis. See, for example, U.S. Patent No. 6,090,619; Wu and Wu, J. Biol. Chem., 263: 14,621 (1988); and Curiel et al, Proc. Natl. Acad. Sci. U.S.A., 88: 8,850 (1991). For example, US Patent No. 6,083,741 discloses the introduction of an exogenous nucleic acid into mammalian cells by associating the nucleic acid with a polycation portion (for example, poly-L-lysine which has 3-100 lysine residues ), which itself is coupled to an integrin-doreceptor binding moiety (for example, a cyclic peptide having the Arg-Gly-Asp sequence (SEQ ID. NO: 5)).
[0102] Self-replicating RNA molecules can be released into cells via amphiphiles. See, for example, U.S. Patent No. 6,071,890. Typically, a nucleic acid molecule can form a complex with the cationic amphiphile. Mammalian cells placed in contact with the complex can easily harvest it.
[0103] Self-replicating RNA can be released as naked RNA (for example, simply as an aqueous solution of RNA), but, to increase cell entry and subsequent intercellular effects, self-replicating RNA is preferably administered in combination with a delivery system, for example, a particulate or emulsion delivery system. A large number of delivery systems are well known to those skilled in the art. These deliberation systems include, for example, liposome-based release (WO 93/24640 for Debs and Zhu (1993); Mannino and Gould-Fogerite (1988) BioTechniques 6 (7): 682-691; US Patent No. 5,279,833 for Rose; WO 91/06309 for Brigham (1991); and Feigner et al (1987) Proc. Natl. Acad. Sci. USA 84: 7.413-7.414), in addition to the use of viral vectors (for example, adenoviral (see , for example, Berns et al (1995) Ann. NY Acad. Sci.772: 95104; Ali et al (1994) Gene Ther.1: 367-384; and Haddada et al (1995) Curr. Top. Microbiol. Immunol. 199 (Part 3): 297-306 for a review), papillomaviruses, retroviral (see, for example, Buchscher et al. (1992) J. Virol. 66 (5) 2.731-2.739; Johann et al . (1992) J. Virol. 66 (5): 1.635-1.640 (1992); Sommerfelt et al., (1990) Virol. 1776: 58-59; Wilson et al. (1989) J. Virol. 63: 2,374 -2,378; Miller et al., J. Virol. 65: 2.220-2.224 (1991); Wong-Staal et al., PCT / US94 / 05700 and Rosenburg and Fauci (1993) in “Fundamental Immunology”, Third Edition Paul ( ed.) Raven Press, Ltd., New York and references cited therein, and Yu et al, Gene Therapy (1994) supra), and adeno-associated virus vectors (see, West et al (1987) Virology 160: 38-47 ; U.S. Patent No. 4,797,368 to Carter et al. (1989); WO 93/24641 to Carter et al (1993); Kotin (1994) Human Gene Therapy 5: 793-801; Muzyczka (1994) J. Clin. Invest. 94: 1,351 and Samulski (supra) for an overview of AAV vectors; see also, U.S. Patent No. 5,173,414 to Lebkowski; Tratschin et al. (1985) Mol. Cell. Biol. 5 (11): 3,251 - 3,260; Tratschin, et al. (1984) Mol. Cell. Biol., 4: 2.072-2.081; Hermonat and Muzyczka (1984) Proc. Natl. Acad. Sci. U.S.A., 81: 6.466-6.470; McLaughlin et al (1988) and Samulski et al. (1989) J. Virol., 63: 3,822-3,828), and the like.
[0104] Three particularly useful delivery systems are (i) liposomes, (ii) non-toxic and biodegradable polymer microparticles, and (iii) submicron cationic oil-in-water emulsions. Liposomes
[0105] Various amphiphilic lipids can form bilayers in an aqueous environment to encapsulate an aqueous nucleus that contains RNA as a liposome. These lipids can have an anionic, cationic or zwitterionic hydrophilic main group. The formation of liposomes from anionic phospholipids dates back to the 1960s, and cationic lipid-forming lipids have been studied since the 1990s. Some phospholipids are anionic, while others are zwitterionic. Suitable phospholipid classes include, without limitation, phosphatidylethanolamines, phosphatidylcholines, phosphatidylserines and phosphatidylglycerols, and some useful phospholipids are listed in Table 2. Useful cationic lipids include, without limitation, dioleoyl trimethylammonium propane (DOTAP), 1,2-diestearyli N-dimethyl-3-aminopropane (DSDMA), 1,2-dioleyloxy-N, N-dimethyl-3-aminopropane (DODMA), 1,2-dilinoleyloxy-N, N-dimethyl-3-aminopropane (DLinDMA), 1 , 2-dilinolenyloxy-N, N-dimethyl-3-aminopropane (DLenDMA). Zwitterionic lipids include, without limitation, acyl zwitterionic lipids and ether zwitterionic lipids. Examples of useful zwitterionic lipids are DPPC, DOPC and dodecylphosphocholine. Lipids can be saturated or unsaturated.
[0106] Liposomes can be formed from a single lipid or from a mixture of lipids. A mixture may comprise: (i) a mixture of anionic lipids (ii) a mixture of cationic lipids (iii) a mixture of zwitterionic lipids (iv) a mixture of anionic lipids and cationic lipids (v) a mixture of anionic lipids and lipids zwitterionics (vi) a mixture of zwitterionic lipids and cationic lipids or (vii) a mixture of anionic lipids, cationic lipids and zwitterionic lipids. Similarly, a mixture can comprise both saturated and unsaturated lipids. For example, a mixture can comprise DSPC (zwitterionic, saturated), DlinDMA (cationic, unsaturated) and / or DMPG (anionic, saturated). When a mixture of lipids is used, not all of the component lipids in the mixture need to be amphiphilic, for example, one or more amphiphilic lipids can be mixed with cholesterol.
[0107] The hydrophilic portion of a lipid can be PEGylated (that is, modified by covalent adhesion of a polyethylene glycol). This modification can increase stability and prevent non-specific adsorption of liposomes. For example, lipids can be conjugated to PEG using techniques such as those disclosed in Heyes et al (2005) J. Controlled Release 107: 276-87.
[0108] A mixture of DSPC, DlinDMA, PEG-DMPG and cholesterol can be used to form liposomes. A separate aspect of the invention is a liposome comprising DSPC, DlinDMA, PEG-DMG and cholesterol. This liposome preferably encapsulates RNA, for example, a self-replicating RNA, for example, which encodes an immunogen.
[0109] Liposomes are usually divided into three groups: multilamellar vesicles (MLV); small unilamellar vesicles (SUV); and large unilamellar vesicles (LUV). MLVs have multiple bilayers in each vesicle, forming several separate aqueous compartments. SUVs and LUVs have a unique bilayer that encapsulates an aqueous core; SUVs typically have a diameter <50nm, and LUVs have a diameter> 50nm. Liposomes useful with the invention are ideally LUVs with a diameter in the range of 50-220 nm. For a composition that comprises a population of LUVs with different diameters: (i) at least 80% per number must have diameters in the range of 20-220 nm, (ii) the average diameter (Zav, by intensity) of the population is ideally 40-200 nm range, and / or (iii) diameters must have a polydispersity index <0.2.
[0110] Methodologies for preparing suitable liposomes are well known in the art; for example, see “Liposomes: MethodsandProtocols”, Volume1: “Pharmaceutical Nanocarriers: Methods and Protocols”, (ed. Weissig), Humana Press, 2009. ISBN 160327359X; Liposome Technology, volumes I, II and III. (ed. Gregoriadis). Informa Healthcare, 2006; and “Functional Polymer Colloids and Microparticles”, Volume 4 (“Microspheres, Microcapsules and Liposomes”), (eds. Arshady and Guyot). Citus Books, 2002. A useful method involves mixing: (i) an ethanolic solution of the lipids (ii) an aqueous solution of the nucleic acid and (iii) buffer, followed by mixing, equilibration, dilution and purification (Heyes et al. (2005) J. Controlled Release 107: 276-87).
[0111] The RNA is preferably encapsulated within the liposomes and, therefore, the liposome forms an outer layer around an aqueous nucleus that contains the RNA. It was found that this encapsulation protects RNA from RNase digestion. Liposomes can include some external RNA (for example, on the surface of the liposomes), but preferably at least half of the RNA (and ideally substantially all of it) is encapsulated. Polymeric microparticles
[0112] Various polymers can form microparticles to encapsulate or adsorb RNA. The use of a substantially non-toxic polymer means that a receptor can safely receive the particles, and the use of a biodegradable polymer means that the particles can be metabolized after release to prevent long-term persistence. Useful polymers are also subject to sterilization, to assist in the preparation of pharmaceutical grade formulations.
[0113] Suitable non-toxic and biodegradable polymers include, without limitation, poly (α-hydroxy acids), polyhydroxybutyric acids, polylactones (including polycaprolactones), polydioxanones, polyvalerolactone, polyarthesters, polyanhydrides, polyacrylates, polycarbonate derivatives, polycarbonates derived from tyrosine, polyester derivatives -amides, and combinations of these.
[0114] In some embodiments, microparticles are formed by poly (α-hydroxy acids), for example, a poly (lactides) (“PLA”), lactide and glycolide copolymers, for example, a poly (D, L- lactide-co-glycolide) (“PLG”), and copolymers of D, L-lactide and caprolactone. Useful PLG polymers include those that have a lactide / glycolide molar ratio that ranges, for example, from 20:80 to 80:20, for example, 25: 75,40: 60,45: 55,55: 45,60: 40.75: 25. Useful PLG polymers include those having a molecular weight between, for example, 5,000-200,000 Da, for example, between 10,000-100,000,20,000-70,000,40,00050,000 Da.
[0115] The microparticles ideally have a diameter in the range of 0.02 μm to 8 μm. For a composition that comprises a population of microparticles with different diameters, at least 80% by number must have diameters in the range of 0.03-7 μm.
[0116] Methodologies for preparing suitable microparticles are well known in the art; for example, see “Functional Polymer Colloids and Microparticles”, Volume 4 (“Microspheres, microcapsules and Liposomes”), (eds. Arshady and Guyot). Citus Books, 2002; "Polymers in Drug Delivery" (eds. Uchegbu and Schatzlein). CRC Press, 2006. (in particular chapter 7) and “Microparticulate Systems for the Delivery of Proteins and Vaccines” (eds. Cohen and Bernstein). CRC Press, 1996. To facilitate RNA adsorption, a microparticle may include a surfactant and / or cationic lipid, for example, as disclosed in O'Hagan et al (2001) J Virology, 15: 9,037-9,043; and Singh et al (2003) Pharmaceutical Research 20: 247-251. An alternative way of producing polymeric microparticles is by molding and curing, for example, as disclosed in WO 2009/132206.
[0117] The microparticles of the invention can have a zeta potential between 40-100 mV. RNA can be adsorbed to microparticles, and adsorption is facilitated by including cationic materials (for example, cationic lipids) in the microparticle. Cationic oil-in-water emulsions
[0118] Oil-in-water emulsions are known to act as adjuvants in influenza vaccines such as, for example, the MF59 ™ adjuvant in the FLUAD ™ product, and the AS03 adjuvant in the PREPANDRIX ™ product. RNA release can be achieved by using an oil-in-water emulsion, as long as the emulsion includes one or more cationic molecules. For example, a cationic lipid can be included in the emulsion to provide a positively charged droplet surface to which the negatively charged RNA can attach.
[0119] The emulsion comprises one or more oils. Suitable oils include those from, for example, an animal (e.g., fish) or a vegetable source. The oil is ideally biodegradable (metabolizable) and biocompatible. Sources for vegetable oils include nuts, seeds and grains. Peanut oil, soy oil, coconut oil and olive oil, the most commonly available, exemplify nut oils. Jojoba oil, for example, obtained from jojoba beans, can be used. Seed oils include safflower oil, cottonseed oil, sunflower seed oil, sesame seed oil and the like. In the grain group, corn oil is the most readily available, but oil from other cereal grains, such as wheat, oats, rye, rice, teff, triticale and the like, can also be used. Esters of glycerol fatty acid 6-10 carbons and 1,2-propanediol, although they do not occur naturally in seed oils, the appropriate materials can be prepared by hydrolysis, separation and esterification starting from the oils of nuts and seeds. Mammalian milk fats and oils are metabolizable and therefore can be used. The procedures for separation, purification, saponification and other means necessary to obtain pure oils from animal sources are well known in the art.
[0120] Most fish contain metabolizable oils that can be readily recovered. For example, cod liver oil, shark liver oils and whale oil, for example, spermaceti, exemplify several of the fish oils that can be used here. Several branched-chain oils are synthesized biochemically in 5-carbon isoprene units and are generally termed terpenoids. Squalane, the saturated analog for squalene, can also be used. Fish oils, including squalene and squalane, are readily available from commercial sources or can be obtained by methods known in the art.
[0121] Other useful oils are tocopherols, particularly in combination with squalene. When the oil phase of an emulsion includes a tocopherol, any of the α, β, Y, δ, ε or £ tocopherols can be used, but α-tocopherols are preferred. D-α-tocopherol and DL-α-tocopherol can both be used. A preferred α-tocopherol is DL-α-tocopherol. A combination of oils comprising squalene and a tocopherol (for example, DL-α-tocopherol) can be used.
[0122] Preferred emulsions comprise squalene, a shark liver oil which is a branched unsaturated terpenoid (C30H50; [(CH3) 2C [= CHCH2CH2C (CH3)] 2 = CHCH2-] 2; 2,6,10,15, 19,23-hexamethyl-2,6,10,14,18,22-tetracosahexaene; CAS R 7683-64-9).
[0123] The oil in the emulsion may comprise a combination of oils, for example, squalene and at least one additional oil.
[0124] The aqueous component of the emulsion can be simple water (for example, water for injection) or it can include additional components, for example, solutes. For example, it can include salts to form a buffer, for example, citrate or phosphate salts, for example, sodium salts. Typical buffers include: a phosphate buffer; a Tris buffer; a borate buffer; a succinate buffer; a histidine buffer; or a citrate buffer. The buffered aqueous phase is preferred, and buffers will typically be included in the 5-20 mM range.
[0125] The emulsion also includes a cationic lipid. Preferably, this lipid is a surfactant that can facilitate the formation and stabilization of the emulsion. Useful cationic lipids usually contain a nitrogen atom that is positively charged under physiological conditions, for example, as a tertiary or quaternary amine. This nitrogen may be in the main hydrophilic group of the amphiphilic surfactant. Useful cationic lipids include, without limitation: 1,2-dioleoyloxy-3- (trimethylammonium) propane (DOTAP), 3 '- [N- (N', N'-dimethylaminoethane) - carbamoyl] cholesterol (DC cholesterol), dimethyldioctadecyl- ammonium (DDA for example, bromide), 1,2-dimyristoyl-3-trimethyl-ammonium-propane (DMTAP), dipalmitoyl (C16: 0) trimethyl ammonium propane (DPTAP), distearoyltrimethylammonium propane (DSTAP). Other useful cationic lipids are: benzalkonium chloride (BAK), benzethonium chloride, cetramide (which contains tetradecyltrimethylammonium bromide and possibly small amounts of dodecyltrimethylammonium bromide and hexadecyltrimethyl ammonium bromide), cetylmethyl chloride (CP) (CTAC), N, N ', N'-polyoxyethylene (10) -N-tallow-1,3-diaminopropane, dodecyltrimethylammonium bromide, hexadecyltrimethyl-ammonium bromide, mixed alkyl-trimethyl-ammonium bromide, benzylimethyldodecylammonium chloride, chlorethodebenzyldimethylhexadecyl-ammonium, benzyltrimethylammoniomethoxide, cetyldimethylethylammonium bromide, dimethyldioctadecyl ammonium bromide (DDAB), methylbenzethonium chloride, decamethonium chloride, methyl trialkyl ammonium chloride, N-chloro-methyl chloride, mixed chloride (2-methyl-4- (1,1,3,3etramethylbutyl) -phenoxy] -ethoxy) ethyl] - benzenemethamonium (DEBDA), dialkyldimethylammonium salts, [1- (2,3-dioleyloxy) -propyl] -N chloride , N, N - trimethylammonium, 1,2-diacyl-3- (trimethylammonium) propane (acyl group = dimiristoil, dipalmitoil, diestearoil, dioleoil), 1,2-diacyl-3 (dimethylammonium) propane (acilgrupo = dimiristoil, dipalmitoil, diestearoil, dioleoil) , 1,2-dioleoyl-3- (4'-trimethyl-ammonium) butanoyl-sn-glycerol, 1,2-dioleoyl ester 3-succinyl-sn-glycerol choline, cholesteryl (4'-trimethylammonium) butanoate), salts N-alkyl pyridinium (for example, cetylpyridinium bromide and cetylpyridinium chloride), N-alkylpiperidinium salts, dipotobola dicationic electrolytes (C12Me6; C12BU6), dialkylglycethylphosphorylcholine, lysolecithin, lysolamine, cholesterol, lysolate, cholesterol, lysolate without limitation, dioctadecylamidoglycylspermine (DOGS), dipalmitoylphosphatidylethanol-starch (DPPES), lipopoly-L (or D) -lysine (LPLL, LPDL), poly (L (or D) - lysine conjugated to N-glutarylphosphate and dihydrogenethylamine dihydrate; pendant amino group (CAGluPhCnN), ditetradecyl ester glu tamate with pendant amino group (C14GluCnN +), cationic cholesterol derivatives, including, without limitation, cholesteryl-3 β-oxysuccinamidoethylenetrimethylammonium salt, cholesteryl-3 β-oxysuccinamidoethylene-dimethylamine, cholesteryl-3-β-carboxymethylamine carboxyamidoethylenedimethylamine. Other useful cationic lipids are described in US 2008/0085870 and US 2008/0057080, which are incorporated herein by reference. The cationic lipid is preferably biodegradable (metabolizable) and biocompatible.
[0126] In addition to oil and cationic lipid, an emulsion may include a non-ionic surfactant and / or a zwitterionic surfactant. These surfactants include, without limitation: the surfactants of polyoxyethylene sorbitan esters (commonly called Tweens), especially polysorbate 20 and polysorbate 80; copolymers of ethylene oxide (EO), propylene oxide (PO) and / or butylene oxide (BO), sold under the trade name DOWFAX ™, for example, linear block copolymers of EO / PO; octoxynols, which may vary in the number of repetition of ethoxy groups (oxy-1,2-ethanediyl), with octoxynol-9 (Triton X-100 or t-octylphenoxypolyethoxyethanol) being of particular interest; (octylphenoxy) polyethoxyethanol (IGEPALCA-630 / NP-40); phospholipids such as, for example, phosphatidylcholine (lecithin); polyoxyethylene greases derived from lauryl, cetyl, stearyl and oleyl alcohols (known as Brij surfactants), for example, triethylene glycol monolauryl ether (Brij 30); polyoxyethylene-9-lauryl ether; and sorbitan esters (commonly known as Spans), for example, sorbitan trioleate (Span 85) and sorbitan monolaurate. Preferred surfactants for inclusion in the emulsion are polysorbate 80 (Tween 80; polyoxyethylene sorbitan monooleate), Span 85 (sorbitan trioleate), lecithin and Triton X-100.
[0127] Mixtures of these surfactants can be included in the emulsion; for example, Tween 80 / Span 85 mixtures or Tween 80 / Triton-X100 mixtures. A combination of a polyoxyethylene sorbitan ester such as, for example, polyoxyethylene sorbitan monooleate (Tween 80) and an octoxynol such as, for example, t-octylphenoxy-polyethoxyethanol (Triton X-100), is also suitable. Another useful combination comprises laureth 9 plus a polyoxyethylene sorbitan ester and / or an octoxynol. Useful mixtures may comprise a surfactant with an HLB value in the range of 10-20 (for example, polysorbate 80, with an HLB of 15.0) and a surfactant with an HLB value in the range of 1-10 (for example, sorbitan trioleate, with an HLB of 1.8).
[0128] Preferred amounts of oil (% by volume) in the final emulsion are between 2-20%, for example, 5-15%, 614%, 7-13%, 8-12%. A squalene content of about 4-6% or about 9-11% is particularly useful.
[0129] Preferred amounts of surfactants (% by weight) in the final emulsion are between 0.001% and 8%. For example: polyoxyethylene sorbitan esters (eg polysorbate 80) 0.2 to 4%, in particular between 0.4-0.6%, between 0.45-0.55%, about 0.5% or between 1.5-2%, between 1.82.2%, between 1.9-2.1%, about 2% or 0.85-0.95% or about 1%; sorbitan esters (for example, sorbitan trioleate) 0.02 to 2%, in particular about 0.5%, or about 1%; octyl- or nonylphenoxy polyoxyethanols (e.g., Triton X-100) 0.001 to 0.1%), in particular 0.005 to 0.02%; polyoxyethylene ethers (for example, laureth 9) 0.1 to 8%, preferably 0.1 to 10% and, in particular, 0.1 to 1% or about 0.5%.
[0130] The absolute amounts of oil and surfactant, and their proportion, can be varied within wide limits while still forming an emulsion. Those skilled in the art can easily vary the relative proportions of the components to obtain a desired emulsion, but a weight ratio between 4: 1 and 5: 1 for oil and surfactant is typical (excess oil).
[0131] An important parameter to ensure an emulsion's immunostimulatory activity, particularly in large animals, is the oil droplet size (diameter). The most effective emulsions have a droplet size in the submicron range. Suitably, the droplet sizes will be in the range of 50-750 nm. More suitably, the droplet size is less than 250 nm, for example, less than 200 nm, less than 150 nm. The average droplet size is suitably in the range of 80-180 nm. Ideally, at least 80% (by number) of the emulsion oil droplets are less than 250 nm in diameter and, preferably, at least 90%. Apparatus for determining the average droplet size in an emulsion, and the size distribution, are commercially available. These typically use dynamic light scattering and / or single particle optical detection techniques, for example, the Accusizer ™ and Nicomp ™ series of instruments available from Particle Sizing Systems (Santa Barbara, USA), or the Zetasizer ™ instruments from Malvern Instruments (UK), or Horiba's “Particle Size Distribution Analyzer” instruments (Kyoto, Japan).
[0132] Ideally, the droplet size distribution (by number) has only one maximum, that is, there is a population of single droplets distributed around a mean (mode), instead of having two maxima. Preferred emulsions have a polydispersity <0.4, for example, 0.3, 0.2, or less.
[0133] Suitable emulsions with submicron droplets and a narrow size distribution can be obtained by using microfluidification. This technique reduces the average oil droplet size by propelling jets of inlet components through channels geometrically fixed under high pressure and high speed. These jets come into contact with the canal walls, chamber walls and between them. As a result, shear, impact and cavitation forces cause a reduction in droplet size. Repeated microfluidification steps can be performed until an emulsion is obtained with the desired droplet size and average.
[0134] As an alternative to microfluidification, thermal methods can be used to cause phase inversion. These methods can also provide a submicron emulsion with a narrow particle size distribution.
[0135] Preferred emulsions can be sterilized by filtration, that is, their droplets can pass through a 220 nm filter. In addition to providing sterilization, this procedure also removes any large droplets in the emulsion.
[0136] In certain embodiments, the cationic lipid in the emulsion is DOTAP. The cationic oil-in-water emulsion can comprise from about 0.5 mg / ml to about 25 mg / ml of DOTAP. For example, the cationic oil-in-water emulsion can comprise DOTAP from about 0.5 mg / ml to about 25 mg / ml, from about 0.6 mg / ml to about 25 mg / ml, from about from 0.7 mg / ml to about 25 mg / ml, from about 0.8 mg / ml to about 25 mg / ml, from about 0.9 mg / ml to about 25 mg / ml, from about 1.0 mg / ml to about 25 mg / ml, from about 1.1 mg / ml to about 25 mg / ml, from about 1.2 mg / ml to about 25 mg / ml, from about 1.3 mg / ml to about 25 mg / ml, from about 1.4 mg / ml to about 25 mg / ml, from about 1.5 mg / ml to about 25 mg / ml , from about 1.6 mg / ml to about 25 mg / ml, from about 1.7 mg / ml to about 25 mg / ml, from about 0.5 mg / ml to about 24 mg / ml ml, from about 0.5 mg / ml to about 22 mg / ml, from about 0.5 mg / ml to about 20 mg / ml, from about 0.5 mg / ml to about 18 mg / ml, from about 0.5 mg / ml to about 15 mg / ml, from about 0.5 mg / ml to about 12 mg / ml, from about 0.5 mg / ml to about 10 mg / ml, from about 0.5 mg / ml to about from 5 mg / ml, from about 0.5 mg / ml to about 2 mg / ml, from about 0.5 mg / ml to about 1.9 mg / ml, from about 0.5 mg / ml ml to about 1.8 mg / ml, from about 0.5 mg / ml to about 1.7 mg / ml, from about 0.5 mg / ml to about 1.6 mg / ml, from about 0.6 mg / ml to about 1.6 mg / ml, from about 0.7 mg / ml to about 1.6 mg / ml, from about 0.8 mg / ml to about 1 , 6 mg / ml, about 0.5 mg / ml, about 0.6 mg / ml, about 0.7 mg / ml, about 0.8 mg / ml, about 0.9 mg / ml , about 1.0 mg / ml, about 1.1 mg / ml, about 1.2 mg / ml, about 1.3 mg / ml, about 1.4 mg / ml, about 1, 5 mg / ml, about 1.6 mg / ml, about 12 mg / ml, about 18 mg / ml, about 20 mg / ml, about 21.8 mg / ml, about 24 mg / ml etc. In an exemplary embodiment, the cationic oil-in-water emulsion comprises from about 0.8 mg / ml to about 1.6 mg / ml of DOTAP, for example, 0.8 mg / ml, 1.2 mg / ml ml, 1.4 mg / ml or 1.6 mg / ml.
[0137] In certain embodiments, the cationic lipid is DC cholesterol. The cationic oil-in-water emulsion can comprise DC cholesterol from about 0.1 mg / ml to about 5 mg / ml of DC cholesterol. For example, the cationic oil-in-water emulsion may comprise DC cholesterol from about 0.1 mg / ml to about 5 mg / ml, from about 0.2 mg / ml to about 5 mg / ml, from about 0.3 mg / ml to about 5 mg / ml, from about 0.4 mg / ml to about 5 mg / ml, from about 0.5 mg / ml to about 5 mg / ml, from about 0.62 mg / ml to about 5 mg / ml, from about 1 mg / ml to about 5 mg / ml, from about 1.5 mg / ml to about 5 mg / ml, about 2 mg / ml to about 5 mg / ml, from about 2.46 mg / ml to about 5 mg / ml, from about 3 mg / ml to about 5 mg / ml, from about 3 , 5 mg / ml to about 5 mg / ml, from about 4 mg / ml to about 5 mg / ml, from about 4.5 mg / ml to about 5 mg / ml, from about 0, 1 mg / ml to about 4.92 mg / ml, from about 0.1 mg / ml to about 4.5 mg / ml, from about 0.1 mg / ml to about 4 mg / ml, from about 0.1 mg / ml to about 3.5 mg / ml, from about 0.1 mg / ml to about 3 mg / ml, from about 0.1 mg / ml to about 2, 46 mg / ml, from about 0.1 mg / ml to about 2 m g / ml, from about 0.1 mg / ml to about 1.5 mg / ml, from about 0.1 mg / ml to about 1 mg / ml, from about 0.1 mg / ml to about 0.62 mg / ml, about 0.15 mg / ml, about 0.3 mg / ml, about 0.6 mg / ml, about 0.62 mg / ml, about 0.9 mg / ml, about 1.2 mg / ml, about 2.46 mg / ml, about 4.92 mg / ml etc. In an exemplary embodiment, the cationic oil-in-water emulsion comprises from about 0.62 mg / ml to about 4.92 mg / ml of DC cholesterol, for example, 2.46 mg / ml.
[0138] In certain embodiments, the cationic lipid is DDA. The cationic oil-in-water emulsion can comprise from about 0.1 mg / ml to about 5 mg / ml DDA. For example, the cationic oil-in-water emulsion can comprise ADI of about 0.1 mg / ml to about 5 mg / ml, from about 0.1 mg / ml to about 4.5 mg / ml, from about 0.1 mg / ml to about 4 mg / ml, from about 0.1 mg / ml to about 3.5 mg / ml, from about 0.1 mg / ml to about 3 mg / ml, from about 0.1 mg / ml to about 2.5 mg / ml, from about 0.1 mg / ml to about 2 mg / ml, from about 0.1 mg / ml to about from 1.5 mg / ml, from about 0.1 mg / ml to about 1.45 mg / ml, from about 0.2 mg / ml to about 5 mg / ml, from about 0.3 mg / ml to about 5 mg / ml, from about 0.4 mg / ml to about 5 mg / ml, from about 0.5 mg / ml to about 5 mg / ml, from about 0, 6 mg / ml to about 5 mg / ml, from about 0.73 mg / ml to about 5 mg / ml, from about 0.8 mg / ml to about 5 mg / ml, from about 0 , 9 mg / ml to about 5 mg / ml, from about 1.0 mg / ml to about 5 mg / ml, from about 1.2 mg / ml to about 5 mg / ml, from about 1.45 mg / ml to about 5 mg / ml, from about 2 mg / ml to about 5 mg / ml , from about 2.5 mg / ml to about 5 mg / ml, from about 3 mg / ml to about 5 mg / ml, from about 3.5 mg / ml to about 5 mg / ml, from about 4 mg / ml to about 5 mg / ml, from about 4.5 mg / ml to about 5 mg / ml, about 1.2 mg / ml, about 1.45 mg / ml etc. . Alternatively, the cationic oil-in-water emulsion may comprise ADI at about 20 mg / ml, about 21 mg / ml, about 21.5 mg / ml, about 21.6 mg / ml, about 25 mg / ml. In an exemplary embodiment, the cationic oil-in-water emulsion comprises from about 0.73 mg / ml to about 1.45 mg / ml DDA, for example, 1.45 mg / ml.
[0139] Catheters or similar devices can be used to release the self-replicating RNA molecules of the invention, such as naked RNA or in combination with a delivery system, into a target organ or tissue. Suitable catheters are disclosed, for example, U.S. Patent Nos. 4,186,745, 5,397,307, 5,547,472, 5,674,192 and 6,129,705, all of which are incorporated herein by reference.
[0140] The present invention includes the use of suitable delivery systems, for example, liposomes, polymer microparticles or submicron emulsion microparticles with encapsulated or adsorbed self-replicating RNA, to release a self-replicating RNA molecule encoding two or more CMV proteins, for example, to elicit an immune response alone, or in combination with another macromolecule. The invention includes liposomes, microparticles and submicron emulsions with self-replicating and / or encapsulated, self-replicating RNA molecules, and combinations thereof.
[0141] Self-replicating RNA molecules associated with submicron emulsion liposomes and microparticles can be effectively released to a host cell, and can induce an immune response to the protein encoded by the self-replicating RNA.
[0142] Self-replicating polycistronic RNA molecules that encode CMV proteins, and VRPs produced using polycistronic alphavirus replicons, can be used to form CMV protein complexes in a cell. Complexes include, without limitation, gB / gH / gL; gH / gL; gH / gL / gO; gM / gN; gH / gL / UL128 / UL130 / UL131; and UL128 / UL130 / UL131.
[0143] In some embodiments, combinations of VRPs are released into a cell. Combinations include, without limitation: 1. One VRPdegH / gL and another VRP; 2.UVRPdegH / gLe a degB VRP; 3. One VRPdegH / gL / gO and one VRPdegB; 4. One VRPdegBeumaVRPdegH / gL / UL128 / UL130 / UL131; 5.UVRPdegBeumaVRPdeUL128 / UL130 / UL131; 6.UVRPdegBeumaVRPdegM / gN; 7. One VRB of gB, one VRP of gH / gL and one VRP of UL128 / UL130 / UL131; 8. One VRB of gB, one VRP of gH / gLgO and one VRP of UL128 / UL130 / UL131; 9. One VRP of gB, one VRP of gM / gN, one VRP of gH / gL and one VRP of UL128 / UL130 / UL131; 10. One VRB of gB, one VRP of gM / gN, one VRP of gH / gL / O and one VRP of UL128 / UL130 / UL131; 11. One VRP of gH / gL and one VRP of UL128 / UL130 / UL131; and
[0144] In some embodiments, combinations of self-replicating RNA molecules are released into a cell. Combinations include, without limitation: 1. A self-replicating RNA molecule that encodes gH / gL and a self-replicating RNA molecule that encodes another protein; 2. A self-replicating RNA molecule that encodes gH and gL and a self-replicating RNA molecule that encodes gB; 3. A self-replicating RNA molecule that encodes gH, gL and gO and a self-replicating RNA molecule that encodes gB; 4. A self-replicating RNA molecule encoding gB and a self-replicating RNA molecule encoding gH, gL, UL128, UL130 and UL131; 5. A self-replicating RNA molecule encoding gB and a self-replicating RNA molecule encoding UL128, UL130 and UL131; 6. A self-replicating RNA molecule that encodes gB and a self-replicating RNA molecule that encodes gM and gN; 7. A self-replicating RNA molecule that encodes gB, a self-replicating RNA molecule that encodes gH and gL and a self-replicating RNA molecule that encodes UL128, UL130 and UL131; 8. A self-replicating RNA molecule encoding gB, a self-replicating RNA molecule encoding gH, gL and gO and a self-replicating RNA molecule encoding UL128, UL130 and UL131; 9. A self-replicating RNA molecule that encodes gB, a self-replicating RNA molecule that encodes gM and gN, a self-replicating RNA molecule that encodes gH and gL, and a self-replicating RNA molecule that encodes UL128, UL130 and UL131; 10. A self-replicating RNA molecule that encodes gB, a self-replicating RNA molecule that encodes gM and gN, a self-replicating RNA molecule that encodes gH, gL and gO and a self-replicating RNA molecule that encodes UL128, UL130 and UL131; 11. A self-replicating RNA molecule encoding gH and gL and a self-replicating RNA molecule encoding UL128, UL130 and UL131; and CMV proteins
[0145] Suitable CMV proteins include gB, gH, gL, gO and can be of any CMV strain. Other suitable CMV proteins include UL128, UL130 and UL131, and can be of any CMV strain. For example, CMV proteins can be from CMV strains Merlin, AD169, VR1814, Towne, Toledo, TR, PH, TB40 or Fix. Exemplary CMV proteins and fragments are described herein. These proteins and fragments can be encoded by any suitable nucleotide sequence, including sequences that are codon-optimized or not for expression in a desired host, for example, a human cell. Exemplary sequences of CMV proteins and nucleic acids that encode the proteins are provided in Table 2. Table 2.

CMV gB proteins
[0146] A gB protein can be full-length or it can omit one or more regions of the protein. Alternatively, fragments of a gB protein can be used. The degB amino acids are numbered according to the full lengthegB amino acid sequence (gB FL of CMV) shown in the ID. SEQ. N °: 26, which is 907 amino acids long. Suitable regions of a gB protein, which can be excluded from the full-length protein or included as fragments include: the signal sequence (amino acids 1-24), a disintegrin-like domain of gB-DLD (amino acids 57-146), a site furin cleavage (amino acids 459-460), a heptad repeat region (679-693), a membrane expansion domain (amino acids 751-771) and a cytoplasmic domain of amino acids 771-906. In some embodiments, a gB protein includes amino acids 67-86 (neutralizing epitope AD2) and / or amino acids 532-635 (immunodominant epitope AD1). Specific examples of gB fragments include "gB sol 692", which includes the first 692 gB amino acids, and "gB sol 750", which includes the first 750 gB amino acids. The signal sequence, amino acids 1-24, can be present or absent from gB sol 692 and gB sol 750, as desired. Optionally, the gB protein can be a fragment of gB with 10 amino acids or more in length. For example, the number of amino acids in the fragment can comprise 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325 , 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850 or 875 amino acids. A gB fragment can start at any of the residue numbers 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15, 16,17,18,19, 20,21,22,23,24,25,26,27,28,29,30, 31,32,33,34,35,36,37,38,39,40,41,42,43,44, 45, 46,47,48,49,50,51,52,53,54,55,56,57,58,59,60, 61,62,63,64,65,66,67,68,69, 70,71,72,73,74,75, 76,77,78,79,80,81,82,83,84,85,86,87,88,89,90, 91,92,93,94, 95,96,97,98,99,100,101,102,103, 104,105,106,107,108,109,110,111,112,113,114,115, 116,117, 128,129, 140,141, 152,153, 164,165, 176,177, 188,189, 200,201, 212,213, 224,225, 236,237, 248,249, 26,2,2,2,3,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2 344,345, 356,357, 368,369, 380,381, 392,393, 404,405, 416,417, 428,429, 440,441, 452,453, 464,465, 118,119, 130,131, 142,143, 154,155, 166,167, 178,179, 190,191, 202,203, 214,215, 226,227, 23,2,2,2,2,2,22,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,226,226 286,287, 298,299, 310,311, 322,323, 334,335, 346,347, 358,359, 370,371, 382,383, 394,395, 406,407, 418,419, 430,431, 442,443, 454,455, 466,467, 120,121, 132,133, 144,145, 156,145 57, 168,169, 180,181, 192,193, 204,205, 216,217, 228,229, 240,241, 252,253, 264,265, 276,277, 288,289, 300,301, 312,313, 324,325, 336,337, 348,349, 360,361, 372,373, 384,385, 396,397,4, 42,43,4,4,4,4,4,440,4 456,457, 468,469, 122,123, 134,135, 146,147, 158,159, 170,171, 182,183, 194,195, 206,207, 218,219, 230,231, 242,243, 254,255, 266,267, 278,279, 290,291, 302,303, 314,315, 326,327, 36,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,2,3,2,3,2,2,2,2,2,2,2,2,2,2,2,2,2,3,2,3,2,5,3,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5 do-7 do not do. 398,399, 410,411, 422,423, 434,435, 446,447, 458,459, 470,471, 124,125, 136,137, 148,149, 160,161, 172,173, 184,185, 196,197, 208,209, 220,221, 232,233, 244,245, 256,257, 268,269, 280,281, 32,2,2,22,2,2,2,2,2,2,2,2,2,2,2,2 340,341, 352,353, 364,365, 376,377, 388,389, 400,401, 412,413, 424,425, 436,437, 448,449, 460,461, 472,473, 126,127, 138,139, 150,151, 162,163, 174,175, 186,187, 198,199, 210,211, 222,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,223,223 282,283, 294,295, 306,307, 318,319, 330,331, 342,343, 354,355, 366,367, 378,379, 390,391, 402,403, 414,41 5, 426,427, 438,439, 450,451, 462,463, 474,475, 477,478, 489,490, 501,502, 513,514, 525,526, 537,538, 549,550, 561,562, 573,574, 585,586, 597,598, 609,610, 621,622, 6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,6,66,66,66,66,66,65] 705,706, 717,718, 729,730, 741,742, 753,754, 765,766, 777,778, 789,790, 801,802, 813,814, 825,826, 479,480, 491,492, 503,504, 515,516, 527,528, 539,540, 551,552, 6,5,6,6,6,5,5,6,6,5,5,6,5,5,6,6,5,5,6,6,5,5,6,6,5,6,6,5,5,6,6,5,5,6,6,5,5,6,6,5,5,6,6,5,5,6,6,5,5,6,6,6,5,5,6,6,6,5,5,6,6,5,6,6,5,6,6,6,5,6,6,6,5,5,6,6,6,6,5,6,6,6,5,6,6,5,5,6,6,6,5,5,6,6,6,5,5,6,6,5,5,6,6,5,5,6,6,5,5,6,6,6,5,5,6,6,5,5,6,6,5,5 much most widely yet 647,648, 659,660, 671,672, 683,684, 695,696, 707,708, 719,720, 731,732, 743,744, 755,756, 767,768, 779,780, 791,792, 803,804, 815,816, 827,828, 481,482, 493,494, 505,506, 5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5 about about 5,5- 5,5- 5,5- 5,5- 589.590, 601.602, 613.614, 625.626, 637.638, 649.650, 661.662, 673.674, 685.686, 697.698, 709.710, 721.722, 733.734, 745.746, 757.758, 769.770, 781.782, 793.794, 805.806, 817.818, 829.830, 836,837,838,839,840,841,842,843,844,845,846,847 848,849,850,851,852,853,854,855,856,857,858,859 860,861,862,863,864,865,866,867,868,869,870,87 1 872,873,874,875,876,877,878,879,880,881,882,883 884,885,886,887,888,889,890,891,892,893,894,895 896 or 897. Optionally, a gB fragment can additionally extend at the N-terminus by 5.10.20 or 30 amino acids from the fragment's starting residue. Optionally, a gB fragment can additionally extend at the C-terminus by 5.10, 20 or 30 amino acids from the last residue of the fragment. CMV gH proteins
[0147] In some embodiments, a gH protein is a full-length gH protein (CMV gH FL, SEQ ID NO: 32, for example, which is a 743 amino acid protein). gH has a membrane expansion domain and a domino-cytoplasmic starting from position 716 to position 743. Removing amino acids from 717 to 743 provides a soluble gH (eg CMV gH sol, SEQ ID: NO. 34) . In some embodiments, the gH protein may be a fragment of gH that is 10 amino acids or more in length. For example, the number of amino acids in the fragment can comprise 10,15,20,30,40,50,60,70,80,90,100, 125,150,175,200,225,250,275,300,325,350,375,400, 425,450,475,500,525,550,575,600,625,650,675,700, or 725 amino acids. Optionally, the gH protein can be a fragment of gH with 10 amino acids or more in length. For example, the number of amino acids in the fragment can comprise 10,15,20,30,40,50,60,70, 80,90,100,125,150,175,200,225,250,275,300,325, 350,375,400,425,450,475,500,525,550,575,600,625, 650,675,700 or 725 amino acids. A gH fragment can start at any of the residue numbers: 1,2,3,4, 5,6,7,8,9,10,11,12,13,14,15,16,17,18,19 , 20, 21,22,23,24,25,26,27,28,29,30,31,32,33,34,35, 36,37,38,39,40,41,42,43,44 , 45,46,47,48,49,50, 51,52,53,54,55,56,57,58,59,60,61,62,63,64,65, 66,67,68,69 , 70,71,72,73,74,75,76,77,78,79,80, 81,82,83,84,85,86,87,88,89,90,91,92,93,94 95, 96,97,98,99,100,101,102,103,104,105,106,107, 108,109,110,111,112,113,114,115,116,117,118,119, 120,121,122,123,124,125,126,127,128,129,130,131, 132,133,134,135,136,137,138,139,140,141,142,143, 144,145,146,147,148,149,150,151,152,153,154,155, 156,157,158,159,160,161,162,163,164,165,166,167, 168,169,170,171,172,173,174,175,176,177,178,179, 180,181,182,183,184,185,186,187,188,189,190,191, 192,193,194,195,196,197,198,199,200,201,202,203, 204,205,206,207,208,209,210,211,212,213,214,215, 216,217,218,219,220,221,222,223,224,225,226,227, 228,229,230,231,232,233,234,235,236,237,238,239, 240,241,242,243,244,245,246,247,248,249,250,251, 252,253,254,25 5,256,257,258,259,260,261,262,263, 264,265,266,267,268,269,270,271,272,273,274,275, 276,277,278,279,280,281,282,283,284,285,286,287, 288,289,290,291,292,293,294,295,296,297,298,299, 300,301,302,303,304,305,306,307,308,309,310,311, 312,313,314,315,316,317,318,319,320,321,322,323, 324,325,326,327,328,329,330,331,332,333,334,335, 336,337,338,339,340,341,342,343,344,345,346, 348,349,350,351,352,353,354,355,356,357,358, 360,361,362,363,364,365,366,367,368,369,370, 372,373,374,375,376,377,378,379,380,381,382, 384,385,386,387,388,389,390,391,392,393,394, 396,397,398,399,400,401,402,403,404,405,406, 408,409,410,411,412,413,414,415,416,417,418, 420,421,422,423,424,425,426,427,428,429,430, 432,433,434,435,436,437,438,439,440,441,442, 444,445,446,447,448,449,450,451,452,453,454, 456,457,458,459,460,461,462,463,464,465,466, 468,469,470,471,472,473,474,475,476,477,478, 480,481,482,483,484,485,486,487,488,489,490, 492,493,494,495,496,497,498,499,500,501,502, 504,505,506,507,508,509,510,511,512,513,5 14, 516,517,518,519,520,521,522,523,524,525,526, 528,529,530,531,532,533,534,535,536,537,538, 540,541,542,543,544,545,546,547,548,549,550, 552,553,554,555,556,557,558,559,560,561,562, 564,565,566,567,568,569,570,571,572,573,574, 576,577,578,579,580,581,582,583,584,585,586, 588,589,590,591,592,593,594,595,596,597,598, 600,601,602,603,604,605,606,607,608,609,610, 612,613,614,615,616,617,618,619,620,621,622, 624,625,626,627,628,629,630,631,632,633,634, 636,637,638,639,640,641,642,643,644,645,646, 648,649,650,651,652,653,654,655,656,657,658, 660,661,662,663,664,665,666,667,668,669,670, 672,673,674,675,676,677,678,679,680,681,682, 684,685,686,687,688,689,690,691,692,693,694, 347, 359, 371, 383, 395, 407, 419, 431, 443, 455, 467, 479, 491, 503, 515, 527, 539, 551, 563, 575, 587, 599, 611, 623, 635, 647, 659, 671, 683, 695,696,697,698,699,700,701,702,703,704,705,706,7,7,7,7,7,7,7,7,7,7,7,7,7,7,7,7,7 7,7 7,7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7
[0148] The gH residues are numbered according to the full length gH amino acid sequence (CMV gH FL) shown in the ID. SEQ. No. 32. Optionally, a gH fragment can additionally extend at the N-terminus by 5, 10, 20 or 30 amino acids from the fragment's starting residue. Optionally, a gH fragment can additionally extend at the C-terminus by 5, 10, 20 or 30 amino acids from the last residue of the fragment. CMV gL proteins
[0149] In some embodiments, a gL protein is a full length gL protein (CMV gL FL, SEQ ID NO: 36, for example, which is a 278 amino acid protein). In some embodiments, a fragment of gL can be used. For example, the number of amino acids in the fragment can comprise 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 225 or 250 amino acids. A gL fragment can start at any of the residue numbers 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15, 16,17,18,19, 20,21,22,23,24,25,26,27,28,29,30, 31,32,33,34,35,36,37,38,39,40,41,42,43,44, 45, 46,47,48,49,50,51,52,53,54,55,56,57,58,59,60, 61,62,63,64,65,66,67,68,69, 70,71,72,73,74,75, 76,77,78,79,80,81,82,83,84,85,86,87,88,89,90, 91,92,93,94, 95,96,97,98,99,100,101,102,103, 104,105,106,107,108,109,110,111,112,113,114,115, 116,117,118,119,120,121,122,123,124,125,126,127, 128,129,130,131,132,133,134,135,136,137,138,139 140,141,142,143,144,145,146,147,148,149,150,151 152,153,154,155,156,157,158,159,160,161,162,163 164,165,166,167,168,169,170,171,172,173,174,175 176,177,178,179,180,181,182,183,184,185,186,187 188,189,190,191,192,193,194,195,196,197,198,199 200,201,202,203,204,205,206,207,208,209,210,211 212,213,214,215,216,217,218,219,220,221,222,223 224,225,226,227,228,229,230,231,232,233,234,235 236,237,238,239,240,241,242,243,244,245,246,247 248,249,250,251,252,253,254,255,256,257,258 , 259 260,261,262,263,264,265,266,267or 268.
[0150] The gL residues are numbered according to the full length gL amino acid sequence (CMV gL FL) shown in the ID. SEQ. No. 36. Optionally, a gL fragment may additionally extend at the N-terminus by 5, 10, 20 or 30 amino acids from the fragment's starting residue. Optionally, a gL fragment can additionally extend at the C-terminus by 5, 10, 20 or 30 amino acids from the last residue of the fragment. CMV gO proteins
[0151] In some embodiments, a gO protein is a full-length gO protein (CMV gO FL, SEQ ID NO: 42, for example, which is a 472 amino acid protein). In some embodiments, the gO protein may be a fragment of gO that is 10 amino acids or more in length. For example, the number of amino acids in the fragment can comprise 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325 , 350, 375, 400, 425 or 450 amino acids. A fragment of gO can start at any of the residue numbers: 1.23, 4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19, 20,21,22,23,24,25,26,2728,29,30,31,32,33,34, 35,36,37,38,39,40,41,42,43,44,45, 46,47,48,49, 5051,52,53,54,55,56,57,58,59,60,61,62,63,64, 65,66,67,68,69,70,71, 72,7374,75,76,77,78,79, 80,81,82,83,84,85,86,87,88,89,90,91,92,93,94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 133, 150, 167, 184, 201, 218, 235, 252, 269, 286, 303, 320, 337, 354, 371, 388, 405, 422, 439, 456.
[0152] The gO residues are numbered according to the full length gO amino acid sequence (CMV gO FL) shown in the ID. SEQ. No. 42. Optionally, a gO fragment can additionally extend at the N-terminus by 5, 10, 20 or 30 amino acids from the fragment's starting residue. Optionally, a gO fragment can additionally extend at the C-terminus by 5, 10, 20 or 30 amino acids from the last residue of the fragment. CMV gM proteins
[0153] In some embodiments, a gM protein is a full-length gM protein (CMV gM FL, SEQ ID. NO: 38, for example, which is a 371 amino acid protein). In some embodiments, the gM protein may be a fragment of gM that is 10 amino acids or more in length. For example, the number of amino acids in the fragment can comprise 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325 or 350 amino acids. A gM fragment can start at any of the residue numbers: 1, 2, 3, 4, 5, 6, 7, 8, 9,10,11,12,13,14,15,16,17,18, 19,20,21,22,23, 24,25,26,27,28,29,30,31,32,33,34,35,36,37,38, 39,40,41,42,43, 44,45,46,47,48,49,50,51,52,53, 54,55,56,57,58,59,60,61,62,63,64,65,66,67,68, 69,70,71,72,73,74,75,76,77,78,79,80,81,82,83, 84,85,86,87,88,89,90,91,92,93, 94,95,96,97,98, 99,100,101,102,103,104,105,106,107,108,109,110, 111,112,113,114,115,116,117,118,119,120,121,122, 123,124,125,126,127,128,129,130,131,132,133,134, 135,136,137,138,139,140,141,142,143,144,145,146, 147,148,149,150,151,152,153,154,155,156,157,158, 159,160,161,162,163,164,165,166,167,168,169,170, 171,172,173,174,175,176,177,178,179,180,181,182, 183,184,185,186,187,188,189,190,191,192,193,194, 195,196,197,198,199,200,201,202,203,204,205,206, 207,208,209,210,211,212,213,214,215,216,217,218, 219,220,221,222,223,224,225,226,227,228,229,230, 231,232,233,234,235,236,237,238,239,240,241,242, 243,244,245,246,247,248,249,250,251,252,253 , 254, 255,256,257,258,259,260,261,262,263,264,265,266, 267,268,269,270,271,272,273,274,275,276,277,278, 279,280,281,282,283,284,285,286,287,288,289,290, 291,292,293,294,295,296,297,298,299,300,301,302, 303,304,305,306,307,308,309,310,311,312,313,314, 315,316,317,318,319,320,321,322,323,324,325,326, 327,328,329,330,331,332,333,334,335,336,337,338, 339,340,341,342,343,344,345,346,347,348,349,350, 351,352,353,354,355,356,357,358,359,360 or 361.
[0154] The gM residues are numbered according to the full length gM amino acid sequence (CMV gM FL) shown in the ID. SEQ. No. 38. Optionally, a gM fragment can additionally extend at the N-terminus by 5, 10, 20 or 30 amino acids from the fragment's starting residue. Optionally, a gM fragment can additionally extend at the C-terminus by 5, 10, 20 or 30 amino acids from the last residue of the fragment. CMV gN proteins
[0155] In some embodiments, a gN protein is a full-length gN protein (CMV gN FL, SEQ ID NO: 40, for example, which is a 135-amino acid protein). In some embodiments, the gN protein may be a fragment of gN with 10 amino acids or more in length. For example, the number of amino acids in the fragment can comprise 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100 or 125 amino acids. A gN fragment can start at any of the residue numbers: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124 or 125.
[0156] The gN residues are numbered according to the full length gN amino acid sequence (CMV gN FL) shown in the ID. SEQ. No. 40. Optionally, a gN fragment may additionally extend at the N-terminus by 5, 10, 20 or 30 amino acids from the fragment's starting residue. Optionally, a gN fragment can additionally extend at the C-terminus by 5, 10, 20 or 30 amino acids from the last residue of the fragment. CM12 UL128 proteins
[0157] In some embodiments, a UL128 protein is a full length UL128 protein (UL128 FL from CMV, SEQ ID NO: 44, for example, which is a 171 amino acid protein). In some embodiments, the UL128 protein may be a fragment of UL128 with 10 amino acids or more in length. For example, the number of amino acids in the fragment can comprise 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125 or 150 amino acids. A fragment of UL128 can start at any of the residue numbers: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20,21,22,23,24,25,26,27,28,29,30,31,32,33, 34,35,36,37,38,39,40,41,42,43, 44,45,46,47,48, 49,50,51,52,53,54,55,56,57,58,59,60,61,62,63, 64,65,66,67,68, 69,70,71,72,73,74,75,76,77,78, 79,80,81,82,83,84,85,86,87,88,89,90,91,92,93, 94.95,96,97,98,99,100,101,102,103,104,105,106, 107,108,109,110,111,112,113,114,115,116,117,118, 119,120,121,122,123,124,125,126,127,128,129,130, 131,132,133,134,135,136,147,148,149
[0158] UL128 residues are numbered according to the full length UL128 amino acid sequence (UL128 FL of CMV) shown in the ID. SEQ. No. 44. Optionally, a fragment of UL128 can additionally extend at the N-terminus by 5.10, 20 or 30 amino acids from the fragment's starting residue. Optionally, a fragment of UL128 can additionally extend at the C-terminus by 5.10, 20 or 30 amino acids from the last residue of the fragment. CM1 UL130 proteins
[0159] In some embodiments, a UL130 protein is a full length UL130 protein (UL130 FL from CMV, SEQ ID NO: 46, for example, which is a 214 amino acid protein). In some embodiments, the UL130 protein may be a fragment of UL130 of 10 amino acids or more in length. For example, the number of amino acids in the fragment can comprise 10,15,20,30,40,50,60,70, 80,90,100,125,150,175 or 200 amino acids. A fragment of U130 can start at any of the residue numbers: 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15, 16,17,18,19,20,21,22, 23,24,25,26,27,28,29,30, 31,32,33,34,35,36,37,38,39,40,41,42,43,44,45, 46,47, 48,49,50,51,52,53,54,55,56,57,58,59,60, 61,62,63,64,65,66,67,68,69,70,71,72, 73,74,75, 76,77,78,79,80,81,82,83,84,85,86,87,88,89,90, 91,92,93,94,95,96,97, 98,99,100,101,102,103, 104,105,106,107,108,109,110,111,112,113,114,115, 116,117,118,119,120,121,122,123,124,125,126,127, 128,129,130,131,132,133,134,135,136,137,138,139, 140,141,142,143,144,145,146,147,148,149,150,151, 152,153,154,155,156,157,158,159,160,161,162,163, 164,165,166,167,168,169,170,171,172,173,174,175, 176,177,178,179,180,181,182,183,184,185,186,187, 188,189,190,191,192,193,194,195,196,197,198,199, 200,201,202,203 or 204.
[0160] UL130 residues are numbered according to the full length UL130 amino acid sequence (UL130 FL from CMV) shown in the ID. SEQ. No. 46. Optionally, a fragment of UL130 can additionally extend at the N-terminus by 5.10, 20 or 30 amino acids from the fragment's starting residue. Optionally, a fragment of UL130 can additionally extend at the C-terminus by 5.10, 20 or 30 amino acids from the last residue of the fragment. CM13 UL131 proteins
[0161] In some embodiments, an UL131 protein is a full length UL131 protein (CMV UL131, SEQ ID NO: 48, for example, which is a 129 amino acid protein). In some embodiments, the UL131 protein may be a fragment of UL131 with 10 amino acids or more in length. For example, the number of amino acids in the fragment can comprise 10,15,20,30,40,50,60,70, 80,90,100,125,150,175 or 200 amino acids. A fragment of UL131 can start at any of the residue numbers 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15, 16,17,18,19, 20,21,22,23,24,25,26,27,28,29,30, 31,32,33,34,35,36,37,38,39,40,41,42,43,44, 45, 46,47,48,49,50,51,52,53,54,55,56,57,58,59,60, 61,62,63,64,65,66,67,68,69, 70,71,72,73,74,75, 76,77,78,79,80,81,82,83,84,85,86,87,88,89,90, 91,92,93,94, 95,96,97,98,99,100,101,102,103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119.
[0162] UL131 residues are numbered according to the full length UL131 amino acid sequence (UL131 FL from CMV) shown in the ID. SEQ. N °: 48. Optionally, a fragment of UL131 can additionally extend at the N-terminus by 5.10, 20 or 30 amino acids from the fragment's starting residue. Optionally, a fragment of UL131 can additionally extend at the C-terminus by 5.10, 20 or 30 amino acids from the last residue of the fragment.
[0163] As stated above, the invention relates to recombinant polycistronic nucleic acid molecules that contain a first sequence that encodes a first herpesvirus protein, or fragment thereof, and a second sequence that encodes a second herpesvirus protein, or fragment thereof . Consequently, the foregoing description of certain preferred embodiments, for example, alphavirus VRPs and self-replicating RNAs containing sequences encoding two or more CMV proteins or fragments thereof, is illustrative of the invention, but does not limit the scope of the invention. It will be noted that the sequences that encode CMV proteins in these preferred modalities can be replaced with sequences that encode proteins, for example, gH and gL, or of these, which are 10 amino acids in length or more, from other herpesviruses, such as, HHV -1, HHV-2, HHV-3, HHV-4, HHV-6, HHV-7 and HHV-8. For example, suitable VZV (HHV-3) proteins include gB, gE, gH, gI and gL, and fragments thereof, which are 10 amino acids in length or more, and can be of any strain of VZV. For example, VZV proteins or fragments thereof may be from the VZV strains pOka, Dumas, HJO, CA123 or DR. These exemplary VZV proteins, and fragments thereof, can be encoded by any suitable nucleotide sequence, including sequences that are codon-optimized or not for expression in a desired host, for example, a human cell. Exemplary sequences of VZV proteins are provided here.
[0164] For example, in one embodiment, the polycistronic nucleic acid molecule contains a first sequence that encodes the VZV gH protein or fragment thereof, and a second sequence that encodes a VZV gL protein or fragment thereof.
[0165] In some embodiments, each of the sequences encoding a herpesvirus protein or fragment that are present in the polycistronic nucleic acid molecule is operationally linked to its own control elements. For example, each of the sequences that encode a herpesvirus protein or fragment is operationally linked to its own subgenomic promoter. Thus, the polycistronic nucleic acid molecule, for example, an alphavirus replicon, can contain two, three, four, or five subgenomic promoters, each of which controls the expression of a herpesvirus protein or fragment. When this type of polycistronic nucleic acid molecule is a self-replicating RNA, for example, an alphavirus replicon, it can be packaged as a VRP, or be associated with or formulated with an RNA delivery system. METHODS AND USES
[0166] In some embodiments, self-replicating RNA molecules or VRPs are administered to an individual to stimulate an immune response. In these embodiments, the self-replicating RNA molecules or VRPs are typically present in a composition that can comprise a pharmaceutically acceptable carrier and, optionally, an adjuvant. See, for example, U.S. 6,299,884, U.S. 7,641,911, U.S. 7,306,805 and US 2007/0207090.
[0167] The immune response may comprise a humoral immune response, a cell-mediated immune response, or both. In some embodiments, an immune response is induced against each CMV protein released. A cell-mediated immune response can comprise a T cell helper (T) response, a CD8 + cytotoxic T cell response (CTL), or both. In some embodiments, the immune response comprises a humoral immune response, and antibodies are neutralizing antibodies. Neutralizing antibodies block viral infection of cells. CMV infects epithelial cells as well as fibroblast cells. In some modalities, the immune response reduces or prevents infection of both types of cells. Neutralizing antibody responses can be complement-dependent or complement-independent. In some embodiments, the neutralizing antibody response is complement-independent. In some embodiments, the neutralizing antibody response effects cross-neutralization, that is, an antibody generated against an administered composition neutralizes a CMV virus of a different strain than the strain used in the composition.
[0168] A useful measure of antibody potency in the art is "50% neutralization titration". To determine the 50% neutralizing titration, serum from immunized animals is diluted to assess how diluted the serum can be and still retain the ability to block 50% of viruses from entering cells. For example, a titration of 700 means that serum retained the ability to neutralize 50% of viruses after being diluted 700 times. Thus, higher titers indicate more potent neutralizing antibody responses. In some modalities, this titration is in a range that has a lower limit of about 200, about 400, about 600, about 800, about 1,000, about 1,500, about 2,000, about 2,500, about 3,000, about 3,500, about 4,000, about 4,500, about 5,000, about 5,500, about 6,000, about 6,500, or about 7,000. The 50% neutralization titration range may have an upper limit of about 400, about 600, about 800, about 1,000, about 1,500, about 2,000, about 2,500, about 3,000, about 3,500 , about 4,000, about 4,500, about 5,000, about 5,500, about 6,000, about 6,500, about 7,000, about 8,000, about 9,000, about 10,000, about 11,000, about 12,000, about about 13,000, about 14,000, about 15,000, about 16,000, about 17,000, about 18,000, about 19,000, about 20,000, about 21,000, about 22,000, about 23,000, about 24,000, about 25,000 , about 26,000, about 27,000, about 28,000, about 29,000 or about 30,000. For example, the 50% neutralization titration can be about 3,000 to about 6,500. “Around” means about 10% of the quoted value. The neutralization titration can be measured as described in the specific examples, below.
[0169] An immune response can be stimulated by administering VRPs or self-replicating RNA to an individual, typically a mammal, including a human. In some embodiments, the induced immune response is a protective immune response, that is, the response reduces the risk or aggravation of CMV infection. Stimulation of a protective immune response is particularly desirable in some populations particularly at risk for CMV infection and disease. For example, populations at risk include patients undergoing solid organ transplants (SOT), patients undergoing bone marrow transplantation and patients undergoing hematopoietic stem cell transplantation (HSCT). VRPs can be administered to a pre-transplant transplant donor, or to a pre- and / or post-transplant transplant recipient. Since mother-to-child vertical transmission is a common source of infection in infants, administration of VRPs or self-replicating RNA to a woman who may become pregnant is particularly useful.
[0170] Any suitable route of administration can be used. For example, a composition can be administered intramuscularly, intraperitoneally, subcutaneously or transdermally. Some modalities will be administered via an intramucosal route, such as, for example, intra-oral, intranasal, intravaginal and intra-rectal. The compositions can be administered according to any suitable dosage.
[0171] All patents, patent applications and references cited in that disclosure, including nucleotide and amino acid sequences referred to by the accession number, are expressly incorporated herein by reference. The above disclosure is a general description. A more complete understanding can be obtained by reference to the following specific examples, which are provided for illustrative purposes only. EXAMPLE 1 Release of individual CMV antigens using a VRP platform
[0172] Each of the CMV glycoproteins gB and gH induces neutralizing responses, and gB is the dominant antigen among antibodies in human sera that neutralize fibroblast infection (Britt et al (1990) J. Virol. 64 (3): 1.07985 ). The following experiments demonstrate in mice a neutralizing response against these antigens released using a VRP platform.
[0173] Each CMV antigen was cloned into a pcDNA-6His vector (Invitrogen) and tested for protein expression before cloning into an alphavirus replicon vector, pVCR 2.1 SalI / XbaI derived from the plasmid described by Perri et al. (J. Virol. 77 (19): 10.394-10.403 (2003)) producing the constructions shown in Figure 2. pVCR 2.1 SalI / XbaI is a self-replicating RNA vector that, when electroporated with defective capsid and glycoprotein helper RNA , forms an infectious alphavirus particle.
[0174] pVCR vectors were used to make RNA that was electroporated in hamster cub kidney (BHKV) cells in the presence of defective capsid and glycoprotein helper RNAs derived from the Venezuelan equine encephalitis virus (VEE). After electroporation, the supernatant containing secreted alphavirus vector particles (VRPs) was collected, purified, titrated and used for mouse immunization studies. The mice were immunized with 1 x 106 infectious units (UI) / mouse in a series of two immunizations, with an interval of three weeks. Terminal bleeding was done three weeks after the second immunization. Monocistronic gB, gH and gL VRPs
[0175] Two different versions of soluble gB were built: “gB sol 750” devoid of the transmembrane expansion domain and the cytoplasmic domain; and “gB sol 692” also lacking a hydrophobic region (FIG. 2A) and is similar to the construction by Reap et al. A soluble gH devoid of the transmembrane expansion domain and the cytoplasmic domain ("gH sol 716") was also constructed (FIG. 2C). Sera from immunized mice were analyzed in several assays. Immunoblot (data not shown) and immunofluorescence assays were used to confirm specific antibody responses to the antigens. Neutralization assays were used to demonstrate that the aroused antibody responses were able to neutralize CMV infection.
[0176] Sera from immunized mice were examined by immunofluorescence for recognition of gB in 293T cells transfected with constructs expressing gB-6His. The cells were probed with anti-His antibodies (“anti-6His”), a monoclonal antibody to gB (“anti-gB 27-156”) or collected mouse sera pooled. Preimmune serum was negative in all cases. In cells transfected with constructs that express FL-6His gB, fixed and permeabilized, anti-6His staining revealed a surface expression pattern with a punctiform cytoplasmic pattern that most likely corresponds to the endocytic / exocytic traffic pathway. Both anti-gB 27-156 and pooled mouse sera showed a similar pattern of expression. Mouse sera immunized with each of gB FL VRPs, gB sol 750 VRPs and gB sol 692 VRPs showed the same expression pattern.
[0177] Mice immunized with gH FL VRPs and gH sol 716 VRPs produced specific antibodies to gH. Immunofluorescence analysis of 293T cells transfected with constructs that express gH FL-6His detected strong gH recognition by anti-6His, anti-gH and pooled mouse sera. Sera collected from mice immunized with gL VRPs produced a specific antibody response as determined by immunoblot and immunofluorescence analysis. GL VRPs did not elicit a neutralizing response.
[0178] Sera from mice immunized with gB VRPs or gH VRPs were analyzed for the presence of neutralizing antibodies using a CMV neutralization assay. Sera in various dilutions were pre-incubated with CMV TB40UL32EGFP virus (“TB40-GFP”, a clinical isolate genetically modified to express GFP) and then added to ARPE-19 epithelial cells and incubated for 5 days. At 5 days post-infection, GFP-positive cells were counted. In that assay, cells incubated with serum containing neutralizing antibodies had fewer GFP-positive cells compared to cells incubated with viruses alone or with viruses incubated with preimmune sera. Sera from mice immunized with gB VRPs, gB FL VRPs, gB sol 750 VRPs or gB sol 692 VRPs had strong neutralizing activity in the presence of guinea pig complement (50% neutralization titration in a dilution of serum 1: 1,280-1: 2,560; FIG. 3). Sera from mice immunized with gH FL VRPs or gH sol VRPs had some neutralizing activity that was independent of guinea pig complement (FIG. 3). EXAMPLE 2 Construction of polycistronic alphavirus vectors
[0179] CMV produces several multiprotein complexes during infection. To determine if a single replicon that expresses all components of a desired complex can be used to produce the CMV complex in an individual, or if the components of the complex could be co-released by multiple replicon vectors, we designed a platform that allows for controlled expression of multiple CMV proteins.
[0180] An alphavirus vector (pVCR 2.1 SalI XbaI) has been modified to allow the assembly of multiple subgenomic promoters (SGP) and genes of interest (GOI). The ApaI pVCR 2.1 SalI / XbaI site at 11026-31bp was changed from GGGCCC (SEQ ID NO: 7) to GGCGCC (SEQ ID NO: 8). The ClaI and PmlI restriction sites added in the region immediately below the first subgenomic promoter and SalI-XbaI insertion sites. The sequence at 7727-7754 bp has been changed from ctcgatgtacttccgaggaactgatgtg (SEQ ID NO: 9) to ATCGATGTACTTCCGAGGAACTCACGTG (SEQ ID NO: 10).
[0181] A shuttling vector system was designed to allow the insertion of a GOI directly below a SGP using the SalI-XbaI sites. pcDNA 3.1 (-) C has been modified as shown below. Three SalI sites were deleted: positions 1046-1051 bp, 3332-3337 bp and 5519-21.1-3 bp from GTCGAC (SEQ ID NO: 11) to GTCTAC (SEQ ID NO: 12) . pcDNA 3.1 (-) C has been modified to mutate an XbaI site at position 916-921 bp from TCTAGA (SEQ ID NO: 13) to TCAAGA (SEQ ID NO: 14). pcDNA 3.1 (-) C was modified to add a ClaI site and a SacII site at positions 942-947 (ClaI) and 950955 (SacII) bp from ctggatatctgcag (SEQ ID NO: 15) for ATCGATATCCGCGG (ID. SEQ N °: 16).
[0182] After the restriction sites have been added and the resulting sequence has been verified, the 7611-7689bp region (ctataactctctacggctaacctgaatggactacgacatagtctagtcgac caagcctctagacggcgcgcccacca) (the following SECR virus encoded ID was used by the following. : SGP SX Not F direct: 5'-ATAAGAATGCGGCCGCCTATAACTCTCTACGGCTAACC-3 '(SEQ ID. N °: 18) SGPS-XClaRreverso: 5'-CCATCGATTGGGTGGGCGCGCCGTCTAG-3' or N °: SEQ. Direct XClaF: 5'-CCATCGATCTATAACTCTCTACGGCTAACC3 '(ID.DESEQ.No: 20) and SGPS-XSacReverse: 5'-TCCCCGCGGTGGGTGGGCGCGCCGTCTAG-3' (ID.DESEQ.N °: 21).
[0183] The amplified regions were added to the vector pcDNA 3.1 (-) C modified to make bridge vectors (pcDNA SV) between appropriate sites (NotI-ClaI or ClaI-SacII). The insertion of the NotI-SGP Sal-Xba-ClaI forms the pcDNA SV 2 cassette, the insertion of the ClaI-SGP Sal-Xba-SacII forms the pcDNA SV 3 cassette. These SV cassettes were sequenced. The pcDNA SV 2 cassette contains an additional 12 bp between the XbaI site and the ClaI site (CCACTGTGATCG) (SEQ ID NO: 22), because the Clal site has not been cut in the pcDNA SV 2 vector cassette. PmlI was therefore added. For the pcDNASV 2 cassette, the PmlI site was inserted at 1012 bp (CACGTG) (ID. DESEQ. N °: 23). For cassette 3, the PmlI site was added at 935-940 bp (ACTGTG (SEQ ID NO: 24) was changed to CACGTG (SEQ ID NO: 23).
[0184] For each polycistronic vector, the first gene was inserted directly into the modified pVCR 2.1 vector using the SalI-XbaI sites. The second gene was ligated into the pcDNA SV 2 cassette using SalI-XbaI and excised using NotI-PmlI, NotI-SacII or PCRed using primers for NotI-ClaI and digested using NotI and ClaI. The resulting insert, SGP-SalI-GOI-Xba, was ligated into the modified pVCR 2.1 vector using the NotI-PmlI, NotI-SacII or NotI-ClaI sites. The NotI-ClaI insert was used only when a desired gene in the construct contained a PmlI site.
[0185] In some cases, a third gene was ligated into the pcDNA SV 3 cassette using SalI-XbaI and excised using PmlI-SacII or PCRed using primers for ClaI-SacII and digested using ClaI and SacII. The resulting insert, SGP-SalI-GOI-XbaI, was ligated into the modified pVCR 2.1 vector using PmlI-SacII or ClaI-SacII.
[0186] Digestion with SalI-XbaI was used to validate the construction of polycistronic vector DNA. After digestion with SalI-XbaI, agarose gel electrophoresis was performed to confirm the presence of GOIs. The polycistronic vector DNA was then linearized with PmeI overnight, purified using the Qiagen PCR purification kit, and used as a template to make the RNA using the Ambion mMessage mMachine kit. The quality of the RNA was verified by processing an aliquot of the sample on an RNA agarose gel. Expression by a polycistronic vector
[0187] Fluorescent proteinsGFP (green fluorescent protein) and mCherry (red fluorescent protein) were used as the GOIs to assess the ability of the polycistronic vector to express the two proteins. We prepared a bicistronic vector in which GFP could be expressed using a first subgenomic promoter and mCherry would be expressed by a second subgenomic promoter (FIG. 4A). Polynucleotides containing coding sequences for these proteins were inserted using SalI-XbaI sites. The first polynucleotide (GFP) was inserted directly into the modified alphavirus replicon vector. The second polynucleotide (mCherry) was inserted first into a bridge vector that contains a subgenomic promoter directly above the coding sequence. A fragment containing both the second genomic engine and the second polynucleotide was isolated and ligated into the modified dealfavirus replicon vector containing the first polynucleotide, providing an alphavirus replicon with multiple subgenomic promoters.
[0188] VRPs were produced in BHKV cells by electroporation of replicon RNAs with defective helper RNAs for Cap and Gly. VRPs were collected 24 hours after electroporation and used to infect BHKV cells at a multiplicity of infection (MOI) of 20 infectious units (UI) per cell.
[0189] The experiment tested four sets of VRPs: a VRP that expresses only GFP; a VRP that expresses mCherry; a VRP that expresses only GFP and a VRP that expresses only mCherry, both in a MOI of 20 IU / cell; and a VRP that contains the bicistronic vector GFP (1) - SGPmCherry (2). VRP-infected BHKV cells were examined 24 hours post-infection to determine the percentage of colocalization. Almost all cells were positive for GFP or mCherry when infected alone. The cells infected with two separate VRPs appeared green or red. Very few cells were yellow, indicating that few cells expressed GFP and mCherry at equal levels and that there was a low level of co-infection. These data were confirmed using FACS analysis (FIG. 4B).
[0190] In contrast, alphavirus-infected cells containing the bicistronic vector GFP (1) -SGPmCherry (2) were all yellow, which indicates approximately equal expression of GFP and mCherry. This study demonstrates that multiple proteins can be successfully expressed by a single polycistronic alphavirus replicon vector. EXAMPLE 3 Production of CMV complexes
[0191] This example demonstrates that CMV protein complexes can be formed in a cell after releasing the complex components by a polycistronic alphavirus replicon vector. GH / gL and gH / gL / gO complexes
[0192] Polycistronic alphavirus gH / gL and gH / gL / gO replicons were constructed as described above (shown schematically in FIG. 5A). VRPs containing gH, gL, gO, gH / gL and gH / gL / gO that encode replicons were produced in BHKV cells as described above and used to infect BHKV cells to demonstrate complex formation in vitro. ARPE-19 cells infected with VRP produced disulfide-linked gH / gL complexes. gO did not detectably alter the association of gH / gL (FIG. 5B).
[0193] Immunofluorescence studies were performed to assess the location of gH and gL released alone and when released using a polycistronic alphavirus to verify the relocation of proteins when co-expressed. The location of gH did not appear to change in the presence or absence of gL or gL / gO. The location of gL changed when in the presence of gH and gH / gO.
[0194] Finally, the association of gH / gL was examined by means of immunoprecipitation. A commercial gH antibody (Genway) was used to investigate the association of gH and gL. In all cases, the gH antibody immunoprecipitated gH efficiently (FIG. 5C). When gH was present, gL was not immunoprecipitated. When gL was expressed in the presence of gH or gH / gO, there was an association of gL with gH (FIG. 5C).
[0195] The relocation of gL in the presence of gH and the association of gH / gL (with or without gO) indicates that all components of the polycistronic alphavirus replicons have been expressed and combined to form a complex. EXAMPLE 4 VRPs that effect the formation of the gH / gL complex in vitro induce a potent immune response to CMV that is qualitatively and quantitatively superior to the immune response to gB VRPs.
[0196] This example demonstrates the induction of robust immune responses to complexes formed by the release of polycistronic gH / gL VRPs or gH / gL / gO VRPs compared to the immune responses obtained using VRPs that release administered single components or single component VRPs in combination or with responses aroused by gB VRPs.
[0197] The mice were infected three times with VRPs administered 3 weeks apart (106 IU per mouse; 5 BalbC mice / group). Sera collected from immunizations with single and polycistronic VRPs were evaluated for neutralizing antibodies using a CMV neutralization assay as described above. The neutralization titration was measured as follows. Various dilutions of sera were pre-incubated with TB40-UL32-EGFP in the presence or absence of guinea pig complement and then added to ARPE-19 epithelial cells or MRC-5 fibroblast cells and incubated for 5 days. After 5 days of infection with the virus, GFP-positive cells were counted. The results for the ARPE-19 cells are shown in FIG. 6A, in FIG. 6B and in FIG. 6C. The results for MRC-5 cells are shown in FIG.7A and FIG.7B.
[0198] Sera from mice immunized with gH FL VRPs had low complement-independent neutralizing activity (FIG. 6A and FIG. 6B). No neutralizing activity was observed using sera from mice immunized only with gL or gO in the presence or absence of guinea pig complement (FIG. 6C). Immunization sera combined with various CMV gB proteins (gB FL, gB sol 750 and gB sol 692) demonstrated strong neutralizing activity in the presence of guinea pig complement, with a 50% neutralization titration in a 1: 1,280 dilution of the sera. However, there was no neutralizing activity in the absence of guinea pig complement in ARPE-19 cells for pooled gB sera. VRPs expressing single CMV proteins (gH or gL VRPs or co-administration of gH, gL and gO- to 106 IU / mouse / VRP VRPs) do not increase neutralizing activity beyond that of gH alone.
[0199] In contrast, mouse sera immunized with gH / gL or bistristronic gH / gL / gO VRPs (1 x 106 IU / mouse) demonstrated robust neutralizing responses. In addition, responses were similar in the presence and absence of guinea pig complement, showing that polycistronic VRPs successfully induced a complement-independent immune response (FIG. 6C). The 50% neutralization titration was at a serum dilution of 1: 3500-6400 + in ARPE-19 cells with CMV TB40-GFP virus. This titration is approximately 34 times higher than the 50% complement-dependent neutralization titration for pooled gB sera.
[0200] Results on MRC-5 fibroblast cells were similar to those on ARPE-19 cells (FIGS. 7A and 7B). Sera from mice immunized with gH / gL or bicistronic VRH or gH / gL / gO VRPs demonstrated strong neutralizing activity compared to VRP-immunized mice absorbing gH alone, gL alone or gO alone, mouse mice immunized by co-administration of gH and VRVRPs from gH and VRPs. or co-administration of gH VRPs, gL VRPs and gO VRPs. These results demonstrate that the administration of polycistronic VRPs induced an immune response that provides good complement-independent neutralization of CMV infection of fibroblast cells. To assess the amplitude and potency of gH / gL immune sera against different strains of CMV, we compared the ability of sera to block infection of fibroblasts and epithelial cells with six different CMV strains. Figure 8 shows that gH / gLneutrals potentiate the infection of both types of cells with a wide range of strains.
[0201] These data also demonstrate strong neutralizing activity for mice sera immunized with polycistronic VRPs, but not with mixed pools of VRPs that express only one protein. This shows that polycistronic replicons that encode the components of a protein complex in a single replicon result in efficient production of the complex in situ. Furthermore, since CMV proteins from the Merlin strain were used to stimulate these responses, the in vitro data obtained using the TB40 strain of the CMV virus demonstrate that the neutralizing antibodies induced by the release of polycistronic VRPs are cross-neutralizing antibodies. EXAMPLE 5 RNA synthesis
[0202] Plasmid DNA encoding alphavirus replicons (see FIGS. 14-16) served as a model for RNA synthesis in vitro. Alphavirus replicons contain the genetic elements necessary for RNA replication, but lack those that encode gene products necessary for particle assembly; The structural genes of the alphavirus genome are replaced by sequences that encode a heterologous protein. After releasing the replicons to eukaryotic cells, the positive stranded RNA is translated to produce four non-structural proteins, which together replicate the genomic RNA and transcribe abundant subgenomic mRNAs that encode the heterologous gene product or the gene of interest (GOI). Due to the lack of expression of the structural proteins of alphavirus, replicons are unable to induce the generation of infectious particles. A bacteriophage promoter (T7 or SP6) above the alphavirus cDNA facilitates the synthesis of replicon RNA in vitro and the hepatitis delta virus (HDV) ribozyme just below the poly (A) tail generates the correct 3 'end by through its self-cleavage activity.
[0203] In order to allow the formation of an antigenic protein complex, the expression of the individual components of that complex in the same cell is of fundamental importance. In theory, this can be achieved by co-transfecting cells with the genes that encode the individual components. However, in the case of alphavirus replicon RNAs released non-viral or by VRP, this strategy is prevented by inefficient co-release of multiple RNAs to the same cell or, alternatively, by inefficient launch of multiple self-replicating RNAs in one individual cell. A potentially more efficient way to facilitate the co-expression of components of a protein complex is to release the respective genes as part of the same self-replicating RNA molecule. For this purpose, we have designed alphavirus replicon constructs that encode multiple genes of interest. Each GOI is preceded by its own subgenomic promoter, which is recognized by the alphavirus transcription machinery. In this way, multiple species of subgenomic messenger RNA are synthesized in an individual cell, which allows the assembly of multicomponent protein complexes.
[0204] After linearizing the plasmid DNA below the HDV ribozyme with a suitable restriction endonuclease, the transcripts were synthesized in vitro using bacteriophage T7-derived DNA-dependent RNA polymerase. Transcriptions were performed for 2 hours at 37 ° C in the presence of 7.5 mM of each of the nucleoside triphosphates (ATP, CTP, GTP and UTP) following the instructions provided by the manufacturer (Ambion, Austin, TX). After transcription, the model DNA was digested with TURBO DNase (Ambion, Austin, TX). The replicon RNA was precipitated with LiCl and reconstituted in nuclease-free water. Uncovered RNA was covered post-transcriptionally with vaccinia virus covering enzyme (VCE) using the ScriptCap m7G covering system (Epicenter Biotechnologies, Madison, WI) as defined in the user manual. Post-transcribed open RNA was precipitated with LiCl and reconstituted in nuclease-free water. The concentration of the RNA samples was determined by measuring the optical density at 260 nm. The integrity of the in vitro transcripts was confirmed by denaturing agarose gel electrophoresis. Lipid nanoparticle formulation (LNP)
[0205] 1,2-dilinoleyloxy-N, N-dimethyl-3-aminopropane (DlinDMA) was synthesized using a previously published procedure [Heyes, J., Palmer, L., Bremner, K., MacLachlan, I. “Cationic Lipide Saturation Influences Intracellular Delivery of Encapsulated Nucleic Acids ”, Journal of Controlled Release, 107: 276-287 (2005)]. 1,2- Diaestearoil-sn-glicero-3-phosfocolina (DSPC) was acquired from Genzyme. Cholesterol was obtained from Sigma-Aldrich (St. Lois, MO). 1,2-Dimiristoil-sn-glycero-3-phosphoethanolamine-N- [methoxy (polyethylene glycol) -2000] (ammonium salt) (PEG DMG 2000) was obtained from Avanti Polar Lipids.
[0206] LNPs (RV01 (14)) were formulated using the following method: batch of 150 μg, (hollow PES fibers and without mustang): fresh stock solutions of lipid in ethanol were prepared; 37 mg of DlinDMA, 11.8 mg of DSPC, 27.8 mg of cholesterol and 8.07 mg of PEG DMG 2000 were weighed and dissolved in 7.55 ml of ethanol. The freshly prepared lipid stock solution was gently stirred at 37 ° C for about 15 minutes to form a homogeneous mixture. Next, 453μl of the stock was added to 1.547 ml of ethanol to produce a 2 ml working lipid stock solution. This amount of lipids was used to form LNPs with 150 μg of RNA in an 8: 1 ratio of N: P (nitrogen to phosphate). The ionizable nitrogen in DlinDMA (the cationic lipid) and phosphates in RNA are used for this calculation. It was assumed that each μg of self-replicating RNA molecule contains 3 nanomoles of anionic phosphate, it was assumed that each μg of DlinDMA contains 1.6 cationic nitrogen nanomolecules. A 2 mlt working RNA solution was also prepared from a stock solution of approximately 1 μg / μl, in 100 mM of citrate buffer (pH 6) (Teknova). Three 20 ml glass bottles (with stir bars) were rinsed with RNase Away solution (Molecular BioProducts) and washed with plenty of MilliQ water before use to decontaminate the RNA bottles. One of the vials was used for the RNA working solution and the others for collecting the lipid and RNA mixtures (as described later). The working solutions of lipid and RNA were heated to 37 ° C for 10 min before being loaded into 3cc luer-lok syringes (BD Medical). Two ml of citrate buffer (pH 6) was loaded into another 3 cc syringe. Syringes containing RNA and lipids were connected to a “T” mixer (PEEK ™ junction with 500 μm inside diameter) using FEP tubing ([fluorinated ethylene-propylene] 2 mm inside diameter x 3 mm outside diameter, Idex Health Science, Oak Harbor, WA). The outlet of the “T” mixer was also a FEP pipe (2 mm internal diameter x 3 mm). The third syringe containing the citrate buffer was connected to a separate piece of tubing (2 mm inner diameter x 3 mm outer diameter). All syringes were then conducted at a flow rate of 7 ml / min using a syringe pump (from kdScientific, model No. KDS-220). The tube outlets were positioned to collect the mixtures in a 20 ml glass flask (while shaking). The stirring bar was removed and the ethanol / aqueous solution was allowed to equilibrate to room temperature for 1 h. Then, the mixture was loaded into a 5 cc syringe (BD Medical), which was fitted to a piece of FEP tubing (2 mm inner diameter x 3 mm outer diameter) and, in another 5 cc syringe with equal length of FEP tubing, an equal volume of 100 mM citrate buffer (pH 6) was loaded. The two syringes were conducted at a flow rate of 7 ml / min using a final mixed syringe pump collected in a 20 ml glass vial (while shaking). Then, the LNPs were concentrated to 2 ml and dialyzed against 1015 volumes of PBS IX (from Teknova) using the tangential flow filtration system (TFF) before recovery of the final product. The TFF system and hollow fiber filtration membranes were purchased from Spectrum Labs and were used according to the manufacturer's instructions. Hollow poly (sulfone ether) (PES) filtration membranes (part number P-C1-100E-100-01N) with a pore cut-off value of 100 kD and 20 cm2 of surface area were used. For in vitro and in vivo experiments, the formulations were diluted to the required RNA concentration with PBS IX (from Teknova). Particle size
[0207] Particle size was measured using a Zetasizer Nano ZS (Malvern Instruments, Worcestershire, GB) according to the manufacturer's instructions. Particle sizes are recorded as the average Z with the polydispersity index (pdi). Liposomes were diluted in PBS IX before measurement. Encapsulation efficiency and RNA concentration
[0208] The percentage of encapsulated RNA and the concentration of RNA were determined by the Quant-iT RiboGreen RNA reagent kit (Invitrogen). The manufacturer's instructions were followed in the test. The ribosomal RNA standard provided in the kit was used to generate a standard curve. LNPs obtained by method 1 or methods 2-5 were diluted ten times or one hundred times, respectively, in buffer IX TE (from the kit), before adding the dye. Separately, LNPs were diluted ten or 100 times in IX TE buffer containing 0.5% Triton X (Sigma-Aldrich), before adding the dye. Then, an equal amount of dye was added to each solution and then approximately 180 μl of each solution after adding the dye was loaded in duplicate onto a 96-well tissue culture plate (obtained from VWR, Catalog No. 353072) . The fluorescence (excitation: 485 nm; emission: 528 nm) was read on a microplate reader (from BioTek Instruments, Inc.).
[0209] Triton X was used to break the LNPs, providing a fluorescence reading that corresponds to the amount of total RNA and the sample without Triton X provided the fluorescence that corresponds to the unencapsulated RNA. The% RNA encapsulation was determined as follows: LNP RNA encapsulation (%) = [(Ft-Fi) / Ft] X 100, where Ft is the fluorescence intensity of LNPs with addition of Triton X and Fi is the fluorescence intensity of the LNP solution without the addition of detergent. These values (Ft and Fi) were obtained after subtracting the fluorescence intensity of a blank (buffer IX TE). The concentration of encapsulated RNA was obtained by comparing Ft-Fi with the generated standard curve. All LNP formulations were dosed in vivo based on the encapsulated dose. Viral replicon particles (VRP)
[0210] To compare RNA vaccines to traditional vector-based RNA-approaches for obtaining in vivo expression of reporter genes or antigens, we used viral replicon particles (VRPs), produced in BHK cells by the methods described by Perri et al. ( J. Virol. 77 (19): 10.394-10.403 (2003)), which encode the expression of the same antigens as the corresponding RNA constructs. In this system, the antigen consisted of chimeric alphavirus (VCR) replicons derived from the genome of the Venezuelan equine encephalitis virus (VEEV) genetically modified to contain the 3 '(UTR 3') sequences of the Sindbis virus and a packaging signal from the Sindbis virus (PS) (see FIG. 2 by Perri et al). The replicons were packaged in VRPs for their co-electroporation in hamster cub kidney (BHK) cells along with defective helper RNAs encoding the Sindbis virus capsid and glycoprotein genes (see FIG. 2 by Perri et al.) . The VRPs were then collected and partially purified by ultracentrifugation on a sucrose pad, and concentrated in an Amicon concentrator. The resulting VRP stock was titrated by standard methods and inoculated into animals in culture fluid or other isotonic buffers. An alphavirus replicon particle chimera derived from the Venezuelan equine encephalitis virus and the Sindbis virus is a potent gene-based vaccine delivery vector (J. Virol. 77,10,394 10,403). Murine immunogenicity studies
[0211] Groups of 10 male BALB / c mice aged 8-10 weeks and weighing about 20 g were immunized with 1 x 106 IU (VRP) or 1.0 μg (RNA) on day 0, 21 and 42 with bleeding performed 3 weeks after the 2nd vaccination and 3 weeks after the 3rd vaccination. All animals were injected into the quadriceps on both hind legs, each receiving an equivalent volume (50 μl per site). Microneutralization test
[0212] Serum samples were tested for neutralizing antibodies by an infection reduction neutralization test. Serial two-fold dilutions of HI-serum (in DMEM with 10% FBS HI) were added to an equal volume of CMV (strain TB40 or clinical isolate 8819) previously titrated to generate approximately 200IU / 50 μl. Strains VR1814, Towne, AD169 and clinical isolate 8822 were also used. Serum / virus mixtures were incubated for 2 hours at 37 ° C and 25% CO, to allow neutralization of the virus, and then 50 μl of this mixture (containing approximately 200 IU) was inoculated into duplicate wells of ARPE-19 cells. in 96-well plates in half. The plates were incubated for 40-44 hours. Unless otherwise noted, the number of positive infected foci was determined by immunostaining with a CMV IE1 monoclonal antibody conjugated to AlexaFluor 488, followed by automated counting. The neutralization titration is defined as the reciprocal of the serum dilution that produces a 50% reduction in the number of virus-positive foci per well, in relation to the controls (without serum). Immunogenicity of RNA formulated in gH / gL and LNP VRPs
[0213] The A323 replicon which expresses the CMV surface B (gB) glycoprotein, the A160 replicon which expresses the full length H and L glycoprotein membrane complex (gH / gL) and the A322 replicon which expresses the membrane of the soluble form of glycoprotein H and L (gH sol / gL) were used for this experiment. BALB / c mice, 10 animals per group, received bilateral intramuscular vaccinations (50 per paw) on days 0.21 and 42 with VRPs that express gB (1 x 106 IU), VRPs that express gH / gL (1 x 106 IU) , VRPs that express gH sol / gL (1 x 106 IU) and PBS as the controls. The three test groups received self-replicating RNA (A160, A322 or A323) formulated in LNP (RV01 (14)). Serum was collected for immunological analysis on days 39 (3wp2) and 63 (3wp3). Results of
[0214] The size and percentage of RNA encapsulated in the RV01 (14) formulations made for the experiment are shown in Table 3.Table 3.


[0215] 50% neutralizing titrations for terminal sera (day 63, three weeks after the final vaccination) are shown in Table 4.Table 4.

[0216] RNA expressing a full-length form or a presumed soluble form of the HCMV gH / gL complex arouses high titers of neutralizing antibody, as assessed in epithelial cells using two different HCMV strains. The average titrations aroused by the gH / gL RNAs are at least as high as the average titration for the corresponding gH / gL VRPs (see FIG. 17). EXAMPLE 6 Bicyclonic and pentacistronic nucleic acids encoding CMV proteins
[0217] Additional bicistronic and pentacistronic replicas of alphaviruses expressing human cytomegalovirus (HCMV) glycoprotein complexes have been prepared, and are shown schematically in FIGS. 18 and 20. The alphavirus replicons were based on the Venezuelan equine encephalitis virus (VEE). The replicons were packaged in viral replicon particles (VRPs), encapsulated in lipid nanoparticles (LNP) or formulated with a cationic nanoemulsion (CNE). The expression of the encoded HCMV proteins and protein complexes of each of the replicons was confirmed by immunoblot, coimmunoprecipitation and flow cytometry. Flow cytometry was used to verify the expression of the gH / gL / UL128 / UL130 / UL131 pentameric complex by the pentameric replicons encoding the protein components of the complex, using human monoclonal antibodies specific for conformational epitopes present in the pentameric complex (Macagno et al. (2010), J. Virol. 84 (2): 1.005-13). FIG. 19 shows that these antibodies bind to BHKV cells transfected with replicon RNA that expresses the HCMV Hg / gL / UL128 / UL130 / UL131 pentameric complex (A527). Similar results were obtained when the cells were infected with VRPs made by the same replicon construct. This shows that replicons designed to express the pentameric complex actually express the desired antigen, not the potential gH / gL by-product.
[0218] VRPs, RNA encapsulated in LNPs and RNA formulated with CNE were used to immunize Balb / c mice by intramuscular injections in the rear quadriceps. The mice were immunized three times, three weeks apart, and serum samples were collected from each immunization, as well as three weeks after the third immunization and the final immunization. The sera were evaluated in microneutralization assays to measure the potency of the neutralizing antibody response that was triggered by vaccinations. The titrations are expressed as a 50% neutralizing titration.
[0219] The immunogenicity of several different configurations of a bicistronic expression cassette for a VRM-soluble HCMV gH / gL complex was evaluated. FIG. 20 shows that VRPs expressing the full-length gH / gL complex anchored to the membrane aroused potent neutralizing antibodies at slightly higher titers than the soluble complex (gH sol / gL) expressed by a similar bicistronic expression cassette. Changing the order of the genes encoding gH sol and gL or replacing one of the subgenomic promoters with an IRES or an FMDV 2A site does not substantially increase immunogenicity.
[0220] The amplitude and potency of HCMV neutralizing activity in mice sera immunized with VEE / SIN VRPs that express gH / gL were evaluated by using the sera to block the infection of fibroblasts and epithelial cells with different HCMV strains. Table 5 shows that immune gH / gL sera were broadly and potently neutralizing against six different HCMV strains in both cell types in the absence of complement. The addition of complement had a slight negative effect on the neutralizing potency of the sera. Table 5. Neutralizing antibody titers in mice sera immunized with VRPs derived from pVCR that express gH / gL.

[0221] The immunogenicity of encapsulated LNP-RNAs encoding the pentameric complex (A526 and A527) compared to encapsulated LNP-RNA (A160) and VRPs (pVCR-modified gH-SGPgL) expressing gH / gL was evaluated. Table 6 shows that replicons expressing the pentameric complex aroused more neutralizing antibodies than replicons expressing gH / gL. Table 6. Neutralizing antibody titers.

[0222] The VEE-based pentacistronic RNA replicon that elicited the highest titers of neutralizing antibodies (A527) was packaged as VRPs, and the immunogenicity of VRPs was compared with VRPs that express gH / gL and LNP-encapsulated replicons that express gH / gL and pentameric complex. Table 7 shows that VRPs expressing the pentameric complex elicited higher neutralizing antibody titers than VRPs expressing gH / gL. In addition, 106 infectious units of VRPs are at least as potent as 1 μg of encapsulated LNP-RNA when the VRPs and RNA encode the same protein complexes. Table 7. Neutralizing antibody titers. Serums were collected three weeks after the second immunization.


[0223] The amplitude and potency of the neutralizing activity of HCMVsummons decamundongosimmunized with RNA-based complexopentameric RNA (A527) were evaluated using sera to block the infection of fibroblasts and epithelial cells with different strains of HCMV. Table 8 shows that anti-gH / gL / UL128 / UL130 / UL131 immune sera broadly and potently neutralize epithelial cell infection. This effect was complement-independent. In contrast, sera had a reduced or undetectable effect on fibroblast infection. These results are as expected for immune sera that mainly contain specific antibodies to the pentameric complex of gH / gL / UL128 / UL130 / UL131, as the pentameric complex is not necessary for the infection of fibroblasts and, consequently, antibodies to UL128, UL130 and UL131 do not block fibroblast infection (Adler et al (2006), J. Gen. Virol. 87 (Part9): 2.451-60; Wang and Shenk (2005), Proc. Natl. Acad. Sci. USA 102 ( 50): 18.153-8). Thus, these data demonstrate that the pentameric replicons encoding the gH / gL / UL128 / UL130 / UL131 pentameric complex specifically elicit antibodies to the complex in vivo. Table 8. Neutralizing antibody titers in mice sera immunized with the RNA replicon A527 encapsulated in LNPs. The replicon expresses the HCMV pentameric complex using subgenomic promoters and IRESes.

[0224] To verify whether bicistronic and pentacistronic replicons that express gH / gL and pentameric complexes would elicit neutralizing antibodies in different formulations, cotton rats were immunized with bicistronic or pentacistronic replicons mixed with a cationic nanoemulsion (CNE). Table 9 shows that replicons in CNE elicited neutralizing antibody titrations comparable to those of the same replicons encapsulated in LNPs.Table 9. Neutralizing antibody titrations. Serums were collected three weeks after the second immunization.

EXAMPLE 7 Replicons encoding VZV proteins
[0225] Nucleic acids encoding VZV proteins were cloned into a VEE replicon vector to produce monocistronic replicons that encode gB, gH, gL, gE and gI, and to produce bicistronic replicons that encode gH / gL or gE / gI. In bicistronic replicons, the expression of each VZV open reading frame was directed by a separate subgenomic promoter.
[0226] To prepare replicon RNA, plasmid encoding the replicon was linearized by digestion with PmeI, and the linearized plasmid was extracted with phenol / chloroform / isoamyl alcohol, precipitated in sodium acetate / ethanol and resuspended in 20 μl of free water of RNase.
[0227] RNA was prepared by in vitro transcription of 1 μg of linearized DNA using the MEGAscript T7 kit (AMBION # AM 1333). A 20 μl reaction was prepared according to the manufacturer's instructions without a cap analogue, and incubated for 2 hours at 32 ° C. TURBO DNase (1 μl) was added, and the mixture was incubated for 30 minutes at 32 ° C. RNase-free water (30 μl) and ammonium acetate solution (30 μl) were added. The solution was mixed and cooled for at least 30 minutes at -20 ° C. Then, the solution was centrifuged at maximum speed for 25 minutes at 4 ° C. The supernatant was discarded, and the pellet was rinsed with 70% ethanol, and again centrifuged at maximum speed for 10 minutes at 4 ° C. The pellet was air-dried and resuspended in 50 μl of RNase-free water. The concentration of RNA was measured and the quality was checked on a denaturing gel.
[0228] The RNA was covered using the ScriptCap m7G Capping System (Epicenter # SCCE0625). The reaction was scheduled by combining RNA and RNase-free water. The RNA was then denatured for 5-10 minutes at 65 ° C. The denatured RNA was transferred quickly to ice and the following reagents were added in the following order: Capping ScriptCap Buffer, 10 mM GTP, 2 mM freshly prepared SAM, RNase ScriptGuard inhibitor, and Capping ScriptCap enzyme. The mixture was incubated for 60 minutes at 37 ° C. The reaction was stopped by adding RNase-free water and 7.5 M LiCl, well mixed and the mixture was stored for at least 30 minutes at -20 ° C. Then, the mixture was centrifuged at maximum speed for 25 minutes at 4 ° C, the pellet was rinsed with 70% ethanol, again centrifuged at maximum speed for 10 minutes at 4 ° C and the pellet was air-dried. The pellet was resuspended in RNase-free water. The concentration of RNA was measured and the quality was checked on a denaturing gel. RNA transfection
[0229] Cells (BHK-V cells) were seeded in 6-well plates and brought up to 90-95% confluence at the time of transfection. For each transfection, 3 g of RNA was diluted in 50 ml of OPTIMEM medium in a first tube. Lipofectamine 2000 was added to a second tube that contained 50 ml of OPTIMEM medium. The first and second tubes were combined and stored for 20 minutes at room temperature. The culture media in the 6-well plates were replaced with fresh medium, and the RNA-Lipofectamine complex was placed on the cells and mixed by gently shaking the plate. The plates were incubated for 24 hours at 37 ° C in a CO2 incubator.
[0230] VZV protein expression in transfected cells was assessed by western blot and immunofluorescence. For western blots, lysates from transfected cells were separated by electrophoresis (5 μg of total proteins / streak) and subjected to the blot. A purified viral suspension (7 μg of total protein / streak) derived from the OKA / Merck vaccine strain was used as a positive control. The blots were probed using commercially available antibodies (1: 1,000 dilution) that bind to VZV proteins.
[0231] For immunofluorescence, the transfected cells were collected and seeded in a 96-well plate, and intracellular staining was done using commercially available mouse mAbs (dilution range 1: 1001: 400). The cell pellets were fixed and permeabilized with Citofix-Citoperm solutions. A secondary reagent, goat anti-mouse F (ab ') 2 labeled with Alexa488 (1: 400 dilution of end), was used.
[0232] VZV gE and gI protein expression was detected in cells transfected with monocistronic constructs (gE or gI), and expression of both gE and gI was detected in cells transfected with a bicistronic construction of gE / gI in western blots using commercially available mouse antibodies, 13B1 for gE and 8C4 for gI. VZV gB protein expression was detected in cells transfected with a monocistronic construct that encodes gB by immunofluorescence using commercially available 10G6 antibody. The expression of the VZV gH / gL protein complex was detected by immunofluorescence in cells transfected with gH / gL monocistronic construction or gH / gL monocistronic construction. The gH / gL complex was detected using commercially available SG3 antibody. Murine immunogenicity studies
[0233] Groups of 8 male BALB / c mice aged 6-8 weeks and weighing about 20 g were immunized intramuscularly with 7.0 or 1.0 μg of replicon RNA formulated with a CNE or LNP ( RV01) on days 0, 21 and 42. Blood samples were collected from the immunized animals 3 weeks after the 2nd immunization and 3 weeks after the 3rd immunization. The groups are shown in Table 10. Table 10

Immune response to VZV antigens
[0234] Serum samples were tested for the presence of antibodies to gB, by intracellular staining of MRC-5 cells transfected with VZV replicon. The MRC-5 cells were maintained in Dulbecco's modified Eagle's medium with 10% fetal bovine serum. An inoculum of the VZV Oka strain (obtained from ATCC) was used to infect a culture of MRC-5 cells, and whole infected cells were used to sub-pass the virus. The ratio between infected and uninfected cells was 1:10. Thirty hours after infection, the cells were dispersed by trypsin for seeding in a 96-well plate to perform intracellular staining with pools of mouse sera (dilution range 1: 200 to 1: 800) obtained after immunization. Commercial mAbs were used as controls to quantify the level of infection. The cell pellets were fixed and permeabilized with Citofix-Citoperm solutions. A secondary reagent, F (ab ') 2 goat anti-mouse labeled with Alexa488, was used (final dilution 1: 400).
[0235] Commercial antibodies to gB (10G6), gH (SG3) and gE (13B1 (SBA) and 8612 (Millipore)) were used as positive controls, and each stained infected MRC-5 cells intracellularly. Immune sera obtained 3 weeks after the third immunization with 1 or 7 μg of RNA formulated with CNE or LNP were diluted to 1/200, 1/400 and 1/800 and used to stain infected MRC-5 cells intracellularly. The results are shown in FIG. 21 (Study 1, groups 1, 5, 7, 9, 11, 13 and 15, formulation of CNE) and FIG. 22 (Study 2, groups 1-7, LNP formulation). Neutralization test
[0236] Each immunized mouse serum was serially diluted in two-fold increments starting at 1:20 in a standardized culture medium, and added to an equal volume of VZV suspension in the presence of guinea pig complement. After incubation for 1 hour at 37 ° C, the human epithelial cell line A549 was added. Infected cells can be measured after one week of culture by counting the plaques formed in the culture under a microscope. From the number of plates, the% inhibition of each serum dilution was calculated. A table for each serum sample was drawn up by tabulation of the% inhibition value against the logarithmic scale of the dilution factor. Subsequently, an approximate line of relationship between the dilution factor and the% inhibition was drawn. Next, the 50% neutralization titration was determined as the dilution factor where the cross line at the 50% inhibition value.
[0237] Table 11 shows that sera obtained from mice immunized with monocistronic gE, bicistronic gE / gI and bicistronic gH / gL contained robust titers of neutralizing antibody. Table 11. Neutralization titrations of mouse serums collected in pools immunized with 7 μg of RNA.
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CMV gB FL: 1- atggaaagccggatctggtgcctggtcgtgtgcgtgaacctgtgcatcgtgtgcctgggagccg ccgtgagcagcagcagcaccagaggcaccagcgccacacacagccaccacagcagccacaccac ctctgccgcccacagcagatccggcagcgtgtcccagagagtgaccagcagccagaccgtgtcc cacggcgtgaacgagacaatctacaacaccaccctgaagtacggcgacgtcgtgggcgtgaata ccaccaagtacccctacagagtgtgcagcatggcccagggcaccgacctgatcagattcgagcg gaacatcgtgtgcaccagcatgaagcccatcaacgaggacctggacgagggcatcatggtggtg tacaagagaaacatcgtggcccacaccttcaaagtgcgggtgtaccagaaggtgctgaccttcc ggcggagctacgcctacatccacaccacatacctgctgggcagcaacaccgagtacgtggcccc tcccatgtgggagatccaccacatcaacagccacagccagtgctacagcagctacagccgcgtg atcgccggcacagtgttcgtggcctaccaccgggacagctacgagaacaagaccatgcagctga tgcccgacgactacagcaacacccacagcaccagatacgtgaccgtgaaggaccagtggcacag cagaggcagcacctggctgtaccgggagacatgcaacctgaactgcatggtcaccatcaccacc gccagaagcaagtacccttaccacttcttcgccacctccaccggcgacgtggtggacatcagcc ccttctacaacggcaccaaccggaacgccagctacttcggcgagaacgccgacaagttcttcat cttccccaactacaccatcgtgtccgacttcggcagacccaacagcgctctggaaacccacaga ctggtggcctttctggaacggg ccgacagcgtgatcagctgggacatccaggacgagaagaacg tgacctgccagctgaccttctgggaggcctctgagagaaccatcagaagcgaggccgaggacag ctaccacttcagcagcgccaagatgaccgccaccttcctgagcaagaaacaggaagtgaacatg agcgactccgccctggactgcgtgagggacgaggccatcaacaagctgcagcagatcttcaaca ccagctacaaccagacctacgagaagtatggcaatgtgtccgtgttcgagacaacaggcggcct ggtggtgttctggcagggcatcaagcagaaaagcctggtggagctggaacggctcgccaaccgg tccagcctgaacctgacccacaaccggaccaagcggagcaccgacggcaacaacgcaacccacc tgtccaacatggaaagcgtgcacaacctggtgtacgcacagctgcagttcacctacgacaccct gcggggctacatcaacagagccctggcccagatcgccgaggcttggtgcgtggaccagcggcgg accctggaagtgttcaaagagctgtccaagatcaaccccagcgccatcctgagcgccatctaca acaagcctatcgccgccagattcatgggcgacgtgctgggcctggccagctgcgtgaccatcaa ccagaccagcgtgaaggtgctgcgggacatgaacgtgaaagagagcccaggccgctgctactcc agacccgtggtcatcttcaacttcgccaacagctcctacgtgcagtacggccagctgggcgagg acaacgagatcctgctggggaaccaccggaccgaggaatgccagctgcccagcctgaagatctt tatcgccggcaacagcgcctacgagtatgtggactacctgttcaagcggatgatcgacctgagc agcatctccaccgtggacagcatgatcgccctggacatcgaccccct ggaaaacaccgacttcc gggtgctggaactgtacagccagaaagagctgcggagcagcaacgtgttcgacctggaagagat catgcgggagttcaacagctacaagcagcgcgtgaaatacgtggaggacaaggtggtggacccc ctgcctccttacctgaagggcctggacgacctgatgagcggactgggcgctgccggaaaagccg tgggagtggccattggagctgtgggcggagctgtggcctctgtcgtggaaggcgtcgccacctt tctgaagaaccccttcggcgccttcaccatcatcctggtggccattgccgtcgtgatcatcacc tacctgatctacacccggcagcggagactgtgtacccagcccctgcagaacctgttcccctacc tggtgtccgccgatggcaccacagtgaccagcggctccaccaaggataccagcctgcaggcccc acccagctacgaagagagcgtgtacaacagcggcagaaagggccctggccctcccagctctgat gccagcacagccgcccctccctacaccaacgagcaggcctaccagatgctgctggccctggcta gactggatgccgagcagagggcccagcagaacggcaccgacagcctggatggcagaaccggcac ccaggacaagggccagaagcccaacctgctggaccggctgcggcaccggaagaacggctaccgg cacctgaaggacagcgacgaggaagagaacgtctgataa - 2727 CMV gB FL MESRIWCLVVCVNLCIVCLGAAVSSSSTRGTSATHSHHSSHTTSAAHSRSGSVSQRVTSSQTVS HGVNETIYNTTLKYGDVVGVNTTKYPYRVCSMAQGTDLIRFERNIVCTSMKPINEDLDEGIMVV YKRNIVAHTFKVRVYQKVLTFRRSYAYIHTTYLLGSNTEYVAPPMWEIHHINSHSQCYSSYSRV IAGTVFVAYHRDSYE NKTMQLMPDDYSNTHSTRYVTVKDQWHSRGSTWLYRETCNLNCMVTITT ARSKYPYHFFATSTGDVVDISPFYNGTNRNASYFGENADKFFIFPNYTIVSDFGRPNSALETHR LVAFLERADSVISWDIQDEKNVTCQLTFWEASERTIRSEAEDSYHFSSAKMTATFLSKKQEVNM SDSALDCVRDEAINKLQQIFNTSYNQTYEKYGNVSVFETTGGLVVFWQGIKQKSLVELERLANR SSLNLTHNRTKRSTDGNNATHLSNMESVHNLVYAQLQFTYDTLRGYINRALAQIAEAWCVDQRR TLEVFKELSKINPSAILSAIYNKPIAARFMGDVLGLASCVTINQTSVKVLRDMNVKESPGRCYS RPVVIFNFANSSYVQYGQLGEDNEILLGNHRTEECQLPSLKIFIAGNSAYEYVDYLFKRMIDLS SISTVDSMIALDIDPLENTDFRVLELYSQKELRSSNVFDLEEIMREFNSYKQRVKYVEDKVVDP LPPYLKGLDDLMSGLGAAGKAVGVAIGAVGGAVASVVEGVATFLKNPFGAFTIILVAIAVVIIT YLIYTRQRRLCTQPLQNLFPYLVSADGTTVTSGSTKDTSLQAPPSYEESVYNSGRKGPGPPSSD ASTAAPPYTNEQAYQMLLALARLDAEQRAQQNGTDSLDGRTGTQDKGQKPNLLDRLRHRKNGYR HLKDSDEEENV-- CMV gB sun 750: 1-atggaaagccggatctggtgcctggtcgtgtgcgtgaacctgtgcatcgtgtgcctgggagccg ccgtgagcagcagcagcaccagaggcaccagcgccacacacagccaccacagcagccacaccac ctctgccgcccacagcagatccggcagcgtgtcccagagagtgaccagcagccagaccgtgtcc cacggcgtgaacgagacaatctacaacaccaccctgaagtacggcgacgtcgtgggcgtgaata ccaccaagtacccctacagagtgtgcagcatggcccagggcaccgacctgatcagattcgagcg gaacatcgtgtgcaccagcatgaagcccatcaacgaggacctggacgagggcatcatggtggtg tacaagagaaacatcgtggcccacaccttcaaagtgcgggtgtaccagaaggtgctgaccttcc ggcggagctacgcctacatccacaccacatacctgctgggcagcaacaccgagtacgtggcccc tcccatgtgggagatccaccacatcaacagccacagccagtgctacagcagctacagccgcgtg atcgccggcacagtgttcgtggcctaccaccgggacagctacgagaacaagaccatgcagctga tgcccgacgactacagcaacacccacagcaccagatacgtgaccgtgaaggaccagtggcacag cagaggcagcacctggctgtaccgggagacatgcaacctgaactgcatggtcaccatcaccacc gccagaagcaagtacccttaccacttcttcgccacctccaccggcgacgtggtggacatcagcc ccttctacaacggcaccaaccggaacgccagctacttcggcgagaacgccgacaagttcttcat cttccccaactacaccatcgtgtccgacttcggcagacccaacagcgctctggaaacccacaga ctggtggcctttctggaacgggc cgacagcgtgatcagctgggacatccaggacgagaagaacg tgacctgccagctgaccttctgggaggcctctgagagaaccatcagaagcgaggccgaggacag ctaccacttcagcagcgccaagatgaccgccaccttcctgagcaagaaacaggaagtgaacatg agcgactccgccctggactgcgtgagggacgaggccatcaacaagctgcagcagatcttcaaca ccagctacaaccagacctacgagaagtatggcaatgtgtccgtgttcgagacaacaggcggcct ggtggtgttctggcagggcatcaagcagaaaagcctggtggagctggaacggctcgccaaccgg tccagcctgaacctgacccacaaccggaccaagcggagcaccgacggcaacaacgcaacccacc tgtccaacatggaaagcgtgcacaacctggtgtacgcacagctgcagttcacctacgacaccct gcggggctacatcaacagagccctggcccagatcgccgaggcttggtgcgtggaccagcggcgg accctggaagtgttcaaagagctgtccaagatcaaccccagcgccatcctgagcgccatctaca acaagcctatcgccgccagattcatgggcgacgtgctgggcctggccagctgcgtgaccatcaa ccagaccagcgtgaaggtgctgcgggacatgaacgtgaaagagagcccaggccgctgctactcc agacccgtggtcatcttcaacttcgccaacagctcctacgtgcagtacggccagctgggcgagg acaacgagatcctgctggggaaccaccggaccgaggaatgccagctgcccagcctgaagatctt tatcgccggcaacagcgcctacgagtatgtggactacctgttcaagcggatgatcgacctgagc agcatctccaccgtggacagcatgatcgccctggacatcgaccccctg gaaaacaccgacttcc gggtgctggaactgtacagccagaaagagctgcggagcagcaacgtgttcgacctggaagagat catgcgggagttcaacagctacaagcagcgcgtgaaatacgtggaggacaaggtggtggacccc ctgcctccttacctgaagggcctggacgacctgatgagcggactgggcgctgccggaaaagccg tgggagtggccattggagctgtgggcggagctgtggcctctgtcgtggaaggcgtcgccacctt tctgaagaactgataa - 2256 Cmv gB sol 750 MESRIWCLVVCVNLCIVCLGAAVSSSSTRGTSATHSHHSSHTTSAAHSRSGSVSQRVTS SQTVSHGVNETIYNTTLKYGDVVGVNTTKYPYRVCSMAQGTDLIRFERNIVCTSMKPIN EDLDEGIMVVYKRNIVAHTFKVRVYQKVLTFRRSYAYIHTTYLLGSNTEYVAPPMWEIH HINSHSQCYSSYSRVIAGTVFVAYHRDSYENKTMQLMPDDYSNTHSTRYVTVKDQWHSR GSTWLYRETCNLNCMVTITTARSKYPYHFFATSTGDVVDISPFYNGTNRNASYFGENAD KFFIFPNYTIVSDFGRPNSALETHRLVAFLERADSVISWDIQDEKNVTCQLTFWEASER TIRSEAEDSYHFSSAKMTATFLSKKQEVNMSDSALDCVRDEAINKLQQIFNTSYNQTYE KYGNVSVFETTGGLVVFWQGIKQKSLVELERLANRSSLNLTHNRTKRSTDGNNATHLSN MESVHNLVYAQLQFTYDTLRGYINRALAQIAEAWCVDQRRTLEVFKELSKINPSAILSA IYNKPIAARFMGDVLGLASCVTINQTSVKVLRDMNVKESPGRCYSRPVVIFNFANSSYV QYGQLGEDNEILLGNHRTEECQLPSLKIFIAGNSAYEYVDYLFKRMIDLSSISTVDSMI ALDIDPLENTDFRVLELYSQKELR SSNVFDLEEIMREFNSYKQRVKYVEDKVVDPLPPY LKGLDDLMSGLGAAGKAVGVAIGAVGGAVASVVEGVATFLKN-- CMV gB sol 692: 1-atggaaagccggatctggtgcctggtcgtgtgcgtgaacctgtgcatcgtgtgcctgggagccg ccgtgagcagcagcagcaccagaggcaccagcgccacacacagccaccacagcagccacaccac ctctgccgcccacagcagatccggcagcgtgtcccagagagtgaccagcagccagaccgtgtcc cacggcgtgaacgagacaatctacaacaccaccctgaagtacggcgacgtcgtgggcgtgaata ccaccaagtacccctacagagtgtgcagcatggcccagggcaccgacctgatcagattcgagcg gaacatcgtgtgcaccagcatgaagcccatcaacgaggacctggacgagggcatcatggtggtg tacaagagaaacatcgtggcccacaccttcaaagtgcgggtgtaccagaaggtgctgaccttcc ggcggagctacgcctacatccacaccacatacctgctgggcagcaacaccgagtacgtggcccc tcccatgtgggagatccaccacatcaacagccacagccagtgctacagcagctacagccgcgtg atcgccggcacagtgttcgtggcctaccaccgggacagctacgagaacaagaccatgcagctga tgcccgacgactacagcaacacccacagcaccagatacgtgaccgtgaaggaccagtggcacag cagaggcagcacctggctgtaccgggagacatgcaacctgaactgcatggtcaccatcaccacc gccagaagcaagtacccttaccacttcttcgccacctccaccggcgacgtggtggacatcagcc ccttctacaacggcaccaaccggaacgccagctacttcggcgagaacgccgacaagttcttcat cttccccaactacaccatcgtgtccgacttcggcagacccaacagcgctctggaaacccacaga ctggtggcctttctggaacgggc cgacagcgtgatcagctgggacatccaggacgagaagaacg tgacctgccagctgaccttctgggaggcctctgagagaaccatcagaagcgaggccgaggacag ctaccacttcagcagcgccaagatgaccgccaccttcctgagcaagaaacaggaagtgaacatg agcgactccgccctggactgcgtgagggacgaggccatcaacaagctgcagcagatcttcaaca ccagctacaaccagacctacgagaagtatggcaatgtgtccgtgttcgagacaacaggcggcct ggtggtgttctggcagggcatcaagcagaaaagcctggtggagctggaacggctcgccaaccgg tccagcctgaacctgacccacaaccggaccaagcggagcaccgacggcaacaacgcaacccacc tgtccaacatggaaagcgtgcacaacctggtgtacgcacagctgcagttcacctacgacaccct gcggggctacatcaacagagccctggcccagatcgccgaggcttggtgcgtggaccagcggcgg accctggaagtgttcaaagagctgtccaagatcaaccccagcgccatcctgagcgccatctaca acaagcctatcgccgccagattcatgggcgacgtgctgggcctggccagctgcgtgaccatcaa ccagaccagcgtgaaggtgctgcgggacatgaacgtgaaagagagcccaggccgctgctactcc agacccgtggtcatcttcaacttcgccaacagctcctacgtgcagtacggccagctgggcgagg acaacgagatcctgctggggaaccaccggaccgaggaatgccagctgcccagcctgaagatctt tatcgccggcaacagcgcctacgagtatgtggactacctgttcaagcggatgatcgacctgagc agcatctccaccgtggacagcatgatcgccctggacatcgaccccctg gaaaacaccgacttcc gggtgctggaactgtacagccagaaagagctgcggagcagcaacgtgttcgacctggaagagat catgcgggagttcaacagctacaagcagtgataa -2082 Cmv gB sol 692; MESRIWCLVVCVNLCIVCLGAAVSSSSTRGTSATHSHHSSHTTSAAHSRSGSVSQRVTSSQTVSHGVNET IYNTTLKYGDVVGVNTTKYPYRVCSMAQGTDLIRFERNIVCTSMKPINEDLDEGIMVVYKRNIVAHTFKV RVYQKVLTFRRSYAYIHTTYLLGSNTEYVAPPMWEIHHINSHSQCYSSYSRVIAGTVFVAYHRDSYENKT MQLMPDDYSNTHSTRYVTVKDQWHSRGSTWLYRETCNLNCMVTITTARSKYPYHFFATSTGDVVDISPFY NGTNRNASYFGENADKFFIFPNYTIVSDFGRPNSALETHRLVAFLERADSVISWDIQDEKNVTCQLTFWE ASERTIRSEAEDSYHFSSAKMTATFLSKKQEVNMSDSALDCVRDEAINKLQQIFNTSYNQTYEKYGNVSV FETTGGLVVFWQGIKQKSLVELERLANRSSLNLTHNRTKRSTDGNNATHLSNMESVHNLVYAQLQFTYDT LRGYINRALAQIAEAWCVDQRRTLEVFKELSKINPSAILSAIYNKPIAARFMGDVLGLASCVTINQTSVK VLRDMNVKESPGRCYSRPVVIFNFANSSYVQYGQLGEDNEILLGNHRTEECQLPSLKIFIAGNSAYEYVD YLFKRMIDLSSISTVDSMIALDIDPLENTDFRVLELYSQKELRSSNVFDLEEIMREFNSYKQ- CMV gH FL: 1-atgaggcctggcctgccctcctacctgatcatcctggccgtgtgcctgttcagccacctgctgtccagca gatacggcgccgaggccgtgagcgagcccctggacaaggctttccacctgctgctgaacacctacggcag acccatccggtttctgcgggagaacaccacccagtgcacctacaacagcagcctgcggaacagcaccgtc gtgagagagaacgccatcagcttcaactttttccagagctacaaccagtactacgtgttccacatgccca gatgcctgtttgccggccctctggccgagcagttcctgaaccaggtggacctgaccgagacactggaaag ataccagcagcggctgaatacctacgccctggtgtccaaggacctggccagctaccggtcctttagccag cagctcaaggctcaggatagcctcggcgagcagcctaccaccgtgccccctcccatcgacctgagcatcc cccacgtgtggatgcctccccagaccacccctcacggctggaccgagagccacaccacctccggcctgca cagaccccacttcaaccagacctgcatcctgttcgacggccacgacctgctgtttagcaccgtgaccccc tgcctgcaccagggcttctacctgatcgacgagctgagatacgtgaagatcaccctgaccgaggatttct tcgtggtcaccgtgtccatcgacgacgacacccccatgctgctgatcttcggccacctgcccagagtgct gttcaaggccccctaccagcgggacaacttcatcctgcggcagaccgagaagcacgagctgctggtgctg gtcaagaaggaccagctgaaccggcactcctacctgaaggaccccgacttcctggacgccgccctggact tcaactacctggacctgagcgccctgctgagaaacagcttccacagatacgccgtggacgtgctgaagtc cgga cggtgccagatgctcgatcggcggaccgtggagatggccttcgcctatgccctcgccctgttcgcc gctgccagacaggaagaggctggcgcccaggtgtcagtgcccagagccctggatagacaggccgccctgc tgcagatccaggaattcatgatcacctgcctgagccagaccccccctagaaccaccctgctgctgtaccc cacagccgtggatctggccaagagggccctgtggacccccaaccagatcaccgacatcacaagcctcgtg cggctcgtgtacatcctgagcaagcagaaccagcagcacctgatcccccagtgggccctgagacagatcg ccgacttcgccctgaagctgcacaagacccatctggccagctttctgagcgccttcgccaggcaggaact gtacctgatgggcagcctggtccacagcatgctggtgcataccaccgagcggcgggagatcttcatcgtg gagacaggcctgtgtagcctggccgagctgtcccactttacccagctgctggcccaccctcaccacgagt acctgagcgacctgtacaccccctgcagcagcagcggcagacgggaccacagcctggaacggctgaccag actgttccccgatgccaccgtgcctgctacagtgcctgccgccctgtccatcctgtccaccatgcagccc agcaccctggaaaccttccccgacctgttctgcctgcccctgggcgagagctttagcgccctgaccgtgt ccgagcacgtgtcctacatcgtgaccaatcagtacctgatcaagggcatcagctaccccgtgtccaccac agtcgtgggccagagcctgatcatcacccagaccgacagccagaccaagtgcgagctgacccggaacatg cacaccacacacagcatcaccgtggccctgaacatcagcctggaaaactgcgctttctgtcagtctgccc tgctggaata cgacgatacccagggcgtgatcaacatcatgtacatgcacgacagcgacgacgtgctgtt cgccctggacccctacaacgaggtggtggtgtccagcccccggacccactacctgatgctgctgaagaac ggcaccgtgctggaagtgaccgacgtggtggtggacgccaccgacagcagactgctgatgatgagcgtgt acgccctgagcgccatcatcggcatctacctgctgtaccggatgctgaaaacctgctgataa -2232 Cmv gH FL; MRPGLPSYLIILAVCLFSHLLSSRYGAEAVSEPLDKAFHLLLNTYGRPIRFLRENTTQC TYNSSLRNSTVVRENAISFNFFQSYNQYYVFHMPRCLFAGPLAEQFLNQVDLTETLERY QQRLNTYALVSKDLASYRSFSQQLKAQDSLGEQPTTVPPPIDLSIPHVWMPPQTTPHGW TESHTTSGLHRPHFNQTCILFDGHDLLFSTVTPCLHQGFYLIDELRYVKITLTEDFFVV TVSIDDDTPMLLIFGHLPRVLFKAPYQRDNFILRQTEKHELLVLVKKDQLNRHSYLKDP DFLDAALDFNYLDLSALLRNSFHRYAVDVLKSGRCQMLDRRTVEMAFAYALALFAAARQ EEAGAQVSVPRALDRQAALLQIQEFMITCLSQTPPRTTLLLYPTAVDLAKRALWTPNQI TDITSLVRLVYILSKQNQQHLIPQWALRQIADFALKLHKTHLASFLSAFARQELYLMGS LVHSMLVHTTERREIFIVETGLCSLAELSHFTQLLAHPHHEYLSDLYTPCSSSGRRDHS LERLTRLFPDATVPATVPAALSILSTMQPSTLETFPDLFCLPLGESFSALTVSEHVSYI VTNQYLIKGISYPVSTTVVGQSLIITQTDSQTKCELTRNMHTTHSITVALNISLENCAF CQSALLEYDDTQGVINIMYMHDSDDVLFALDPYNEVVVSSPRTHYLMLLKNGTVLEVTD VVVDATDSRLLMMSVYALSAIIGIYLLYRMLKTC-- CMV gH sun: 1-atgaggcctggcctgccctcctacctgatcatcctggccgtgtgcctgttcagccacctgctgt ccagcagatacggcgccgaggccgtgagcgagcccctggacaaggctttccacctgctgctgaa cacctacggcagacccatccggtttctgcgggagaacaccacccagtgcacctacaacagcagc ctgcggaacagcaccgtcgtgagagagaacgccatcagcttcaactttttccagagctacaacc agtactacgtgttccacatgcccagatgcctgtttgccggccctctggccgagcagttcctgaa ccaggtggacctgaccgagacactggaaagataccagcagcggctgaatacctacgccctggtg tccaaggacctggccagctaccggtcctttagccagcagctcaaggctcaggatagcctcggcg agcagcctaccaccgtgccccctcccatcgacctgagcatcccccacgtgtggatgcctcccca gaccacccctcacggctggaccgagagccacaccacctccggcctgcacagaccccacttcaac cagacctgcatcctgttcgacggccacgacctgctgtttagcaccgtgaccccctgcctgcacc agggcttctacctgatcgacgagctgagatacgtgaagatcaccctgaccgaggatttcttcgt ggtcaccgtgtccatcgacgacgacacccccatgctgctgatcttcggccacctgcccagagtg ctgttcaaggccccctaccagcgggacaacttcatcctgcggcagaccgagaagcacgagctgc tggtgctggtcaagaaggaccagctgaaccggcactcctacctgaaggaccccgacttcctgga cgccgccctggacttcaactacctggacctgagcgccctgctgagaaacagcttccacagatac gccgtggacgtgctgaagtccgg acggtgccagatgctcgatcggcggaccgtggagatggcct tcgcctatgccctcgccctgttcgccgctgccagacaggaagaggctggcgcccaggtgtcagt gcccagagccctggatagacaggccgccctgctgcagatccaggaattcatgatcacctgcctg agccagaccccccctagaaccaccctgctgctgtaccccacagccgtggatctggccaagaggg ccctgtggacccccaaccagatcaccgacatcacaagcctcgtgcggctcgtgtacatcctgag caagcagaaccagcagcacctgatcccccagtgggccctgagacagatcgccgacttcgccctg aagctgcacaagacccatctggccagctttctgagcgccttcgccaggcaggaactgtacctga tgggcagcctggtccacagcatgctggtgcataccaccgagcggcgggagatcttcatcgtgga gacaggcctgtgtagcctggccgagctgtcccactttacccagctgctggcccaccctcaccac gagtacctgagcgacctgtacaccccctgcagcagcagcggcagacgggaccacagcctggaac ggctgaccagactgttccccgatgccaccgtgcctgctacagtgcctgccgccctgtccatcct gtccaccatgcagcccagcaccctggaaaccttccccgacctgttctgcctgcccctgggcgag agctttagcgccctgaccgtgtccgagcacgtgtcctacatcgtgaccaatcagtacctgatca agggcatcagctaccccgtgtccaccacagtcgtgggccagagcctgatcatcacccagaccga cagccagaccaagtgcgagctgacccggaacatgcacaccacacacagcatcaccgtggccctg aacatcagcctggaaaactgcgctttctgtcagtctgccctgctggaa tacgacgatacccagg gcgtgatcaacatcatgtacatgcacgacagcgacgacgtgctgttcgccctggacccctacaa cgaggtggtggtgtccagcccccggacccactacctgatgctgctgaagaacggcaccgtgctg gaagtgaccgacgtggtggtggacgccaccgactgataa -2151 CMV gH sun; MRPGLPSYLIILAVCLFSHLLSSRYGAEAVSEPLDKAFHLLLNTYGRPIRFLRENTTQC TYNSSLRNSTVVRENAISFNFFQSYNQYYVFHMPRCLFAGPLAEQFLNQVDLTETLERY QQRLNTYALVSKDLASYRSFSQQLKAQDSLGEQPTTVPPPIDLSIPHVWMPPQTTPHGW TESHTTSGLHRPHFNQTCILFDGHDLLFSTVTPCLHQGFYLIDELRYVKITLTEDFFVV TVSIDDDTPMLLIFGHLPRVLFKAPYQRDNFILRQTEKHELLVLVKKDQLNRHSYLKDP DFLDAALDFNYLDLSALLRNSFHRYAVDVLKSGRCQMLDRRTVEMAFAYALALFAAARQ EEAGAQVSVPRALDRQAALLQIQEFMITCLSQTPPRTTLLLYPTAVDLAKRALWTPNQI TDITSLVRLVYILSKQNQQHLIPQWALRQIADFALKLHKTHLASFLSAFARQELYLMGS LVHSMLVHTTERREIFIVETGLCSLAELSHFTQLLAHPHHEYLSDLYTPCSSSGRRDHS LERLTRLFPDATVPATVPAALSILSTMQPSTLETFPDLFCLPLGESFSALTVSEHVSYI VTNQYLIKGISYPVSTTVVGQSLIITQTDSQTKCELTRNMHTTHSITVALNISLENCAF CQSALLEYDDTQGVINIMYMHDSDDVLFALDPYNEVVVSSPRTHYLMLLKNGTVLEVTD VVVDATD-- CMV gL fl: 1-atgtgcagaaggcccgactgcggcttcagcttcagccctggacccgtgatcctgctgtggtgct gcctgctgctgcctatcgtgtcctctgccgccgtgtctgtggcccctacagccgccgagaaggt gccagccgagtgccccgagctgaccagaagatgcctgctgggcgaggtgttcgagggcgacaag tacgagagctggctgcggcccctggtcaacgtgaccggcagagatggccccctgagccagctga tccggtacagacccgtgacccccgaggccgccaatagcgtgctgctggacgaggccttcctgga taccctggccctgctgtacaacaaccccgaccagctgagagccctgctgaccctgctgtccagc gacaccgcccccagatggatgaccgtgatgcggggctacagcgagtgtggagatggcagccctg ccgtgtacacctgcgtggacgacctgtgcagaggctacgacctgaccagactgagctacggccg gtccatcttcacagagcacgtgctgggcttcgagctggtgccccccagcctgttcaacgtggtg gtggccatccggaacgaggccaccagaaccaacagagccgtgcggctgcctgtgtctacagccg ctgcacctgagggcatcacactgttctacggcctgtacaacgccgtgaaagagttctgcctccg gcaccagctggatccccccctgctgagacacctggacaagtactacgccggcctgcccccagag ctgaagcagaccagagtgaacctgcccgcccacagcagatatggccctcaggccgtggacgcca gatgataa - 840 CMV gL FL; MCRRPDCGFSFSPGPVILLWCCLLLPIVSSAAVSVAPTAAEKVPAECPELTRRCLLGEV FEGDKYESWLRPLVNVTGRDGPLSQLIRYRPVTPEAANSVLLDEAFLDTLALLYNNPDQ LRALLTLLSSDTAPRWMTVMRGYSECGDGSPAVYTCVDDLCRGYDLTRLSYGRSIFTEH VLGFELVPPSLFNVVVAIRNEATRTNRAVRLPVSTAAAPEGITLFYGLYNAVKEFCLRH QLDPPLLRHLDKYYAGLPPELKQTRVNLPAHSRYGPQAVDAR-- CMV gM FL: 1-atggcccccagccacgtggacaaagtgaacacccggacttggagcgccagcatcgtgttcatgg tgctgaccttcgtgaacgtgtccgtgcacctggtgctgtccaacttcccccacctgggctaccc ctgcgtgtactaccacgtggtggacttcgagcggctgaacatgagcgcctacaacgtgatgcac ctgcacacccccatgctgtttctggacagcgtgcagctcgtgtgctacgccgtgttcatgcagc tggtgtttctggccgtgaccatctactacctcgtgtgctggatcaagatcagcatgcggaagga caagggcatgagcctgaaccagagcacccgggacatcagctacatgggcgacagcctgaccgcc ttcctgttcatcctgagcatggacaccttccagctgttcaccctgaccatgagcttccggctgc ccagcatgatcgccttcatggccgccgtgcactttttctgtctgaccatcttcaacgtgtccat ggtcacccagtaccggtcctacaagcggagcctgttcttcttctcccggctgcaccccaagctg aagggcaccgtgcagttccggaccctgatcgtgaacctggtggaggtggccctgggcttcaata ccaccgtggtggctatggccctgtgctacggcttcggcaacaacttcttcgtgcggaccggcca tatggtgctggccgtgttcgtggtgtacgccatcatcagcatcatctactttctgctgatcgag gccgtgttcttccagtacgtgaaggtgcagttcggctaccatctgggcgcctttttcggcctgt gcggcctgatctaccccatcgtgcagtacgacaccttcctgagcaacgagtaccggaccggcat cagctggtccttcggaatgctgttcttcatctgggccatgttcaccacctgcagagccgtgcgg tacttcagaggcagaggcagcgg ctccgtgaagtaccaggccctggccacagcctctggcgaag aggtggccgccctgagccaccacgacagcctggaaagcagacggctgcgggaggaagaggacga cgacgacgaggacttcgaggacgcctgata - 1119 CMV gMg; MAPSHVDKVNTRTWSASIVFMVLTFVNVSVHLVLSNFPHLGYPCVYYHVVDFERLNMSA YNVMHLHTPMLFLDSVQLVCYAVFMQLVFLAVTIYYLVCWIKISMRKDKGMSLNQSTRD ISYMGDSLTAFLFILSMDTFQLFTLTMSFRLPSMIAFMAAVHFFCLTIFNVSMVTQYRS YKRSLFFFSRLHPKLKGTVQFRTLIVNLVEVALGFNTTVVAMALCYGFGNNFFVRTGHM VLAVFVVYAIISIIYFLLIEAVFFQYVKVQFGYHLGAFFGLCGLIYPIVQYDTFLSNEY RTGISWSFGMLFFIWAMFTTCRAVRYFRGRGSGSVKYQALATASGEEVAALSHHDSLES RRLREEEDDDDEDFEDA-- CMV gN FL: 1-atggaatggaacaccctggtcctgggcctgctggtgctgtctgtcgtggccagcagcaacaaca catccacagccagcacccctagacctagcagcagcacccacgccagcactaccgtgaaggctac caccgtggccaccacaagcaccaccactgctaccagcaccagctccaccacctctgccaagcct ggctctaccacacacgaccccaacgtgatgaggccccacgcccacaacgacttctacaacgctc actgcaccagccacatgtacgagctgtccctgagcagctttgccgcctggtggaccatgctgaa cgccctgatcctgatgggcgccttctgcatcgtgctgcggcactgctgcttccagaacttcacc gccaccaccaccaagggctactgataa -411 CMV gN FL; MEWNTLVLGLLVLSVVASSNNTSTASTPRPSSSTHASTTVKATTVATTSTTTATSTSST TSAKPGSTTHDPNVMRPHAHNDFYNAHCTSHMYELSLSSFAAWWTMLNALILMGAFCIV LRHCCFQNFTATTTKGY-- CMV g 1- atgggcaagaaagaaatgatcatggtcaagggcatccccaagatcatgctgctgattagcatca cctttctgctgctgtccctgatcaactgcaacgtgctggtcaacagccggggcaccagaagatc ctggccctacaccgtgctgtcctaccggggcaaagagatcctgaagaagcagaaagaggacatc ctgaagcggctgatgagcaccagcagcgacggctaccggttcctgatgtaccccagccagcaga aattccacgccatcgtgatcagcatggacaagttcccccaggactacatcctggccggacccat ccggaacgacagcatcacccacatgtggttcgacttctacagcacccagctgcggaagcccgcc aaatacgtgtacagcgagtacaaccacaccgcccacaagatcaccctgaggcctcccccttgtg gcaccgtgcccagcatgaactgcctgagcgagatgctgaacgtgtccaagcggaacgacaccgg cgagaagggctgcggcaacttcaccaccttcaaccccatgttcttcaacgtgccccggtggaac accaagctgtacatcggcagcaacaaagtgaacgtggacagccagaccatctactttctgggcc tgaccgccctgctgctgagatacgcccagcggaactgcacccggtccttctacctggtcaacgc catgagccggaacctgttccgggtgcccaagtacatcaacggcaccaagctgaagaacaccatg cggaagctgaagcggaagcaggccctggtcaaagagcagccccagaagaagaacaagaagtccc agagcaccaccaccccctacctgagctacaccacctccaccgccttcaacgtgaccaccaacgt gacctacagcgccacagccgccgtgaccagagtggccacaagcaccaccggctaccggcccgac agcaactttatgaagtccatca tggccacccagctgagagatctggccacctgggtgtacacca ccctgcggtacagaaacgagcccttctgcaagcccgaccggaacagaaccgccgtgagcgagtt catgaagaatacccacgtgctgatcagaaacgagacaccctacaccatctacggcaccctggac atgagcagcctgtactacaacgagacaatgagcgtggagaacgagacagccagcgacaacaacg aaaccacccccacctcccccagcacccggttccagcggaccttcatcgaccccctgtgggacta cctggacagcctgctgttcctggacaagatccggaacttcagcctgcagctgcccgcctacggc aatctgaccccccctgagcacagaagggccgccaacctgagcaccctgaacagcctgtggtggt ggagccagtgataa CMV gO -1422 FL; MGKKEMIMVKGIPKIMLLISITFLLLSLINCNVLVNSRGTRRSWPYTVLSYRGKEILKK QKEDILKRLMSTSSDGYRFLMYPSQQKFHAIVISMDKFPQDYILAGPIRNDSITHMWFD FYSTQLRKPAKYVYSEYNHTAHKITLRPPPCGTVPSMNCLSEMLNVSKRNDTGEKGCGN FTTFNPMFFNVPRWNTKLYIGSNKVNVDSQTIYFLGLTALLLRYAQRNCTRSFYLVNAM SRNLFRVPKYINGTKLKNTMRKLKRKQALVKEQPQKKNKKSQSTTTPYLSYTTSTAFNV TTNVTYSATAAVTRVATSTTGYRPDSNFMKSIMATQLRDLATWVYTTLRYRNEPFCKPD RNRTAVSEFMKNTHVLIRNETPYTIYGTLDMSSLYYNETMSVENETASDNNETTPTSPS TRFQRTFIDPLWDYLDSLLFLDKIRNFSLQLPAYGNLTPPEHRRAANLSTLNSLWWWSQ- CMV UL128 FL: 1-atgagccccaaggacctgacccccttcctgacaaccctgtggctgctcctgggccatagcagag tgcctagagtgcgggccgaggaatgctgcgagttcatcaacgtgaaccacccccccgagcggtg ctacgacttcaagatgtgcaaccggttcaccgtggccctgagatgccccgacggcgaagtgtgc tacagccccgagaaaaccgccgagatccggggcatcgtgaccaccatgacccacagcctgaccc ggcaggtggtgcacaacaagctgaccagctgcaactacaaccccctgtacctggaagccgacgg ccggatcagatgcggcaaagtgaacgacaaggcccagtacctgctgggagccgccggaagcgtg ccctaccggtggatcaacctggaatacgacaagatcacccggatcgtgggcctggaccagtacc tggaaagcgtgaagaagcacaagcggctggacgtgtgcagagccaagatgggctacatgctgca gtgataa -519 CMV UL128 FL; MSPKDLTPFLTTLWLLLGHSRVPRVRAEECCEFINVNHPPERCYDFKMCNRFTVALRCP DGEVCYSPEKTAEIRGIVTTMTHSLTRQVVHNKLTSCNYNPLYLEADGRIRCGKVNDKA QYLLGAAGSVPYRWINLEYDKITRIVGLDQYLESVKKHKRLDVCRAKMGYMLQ-- CMV UL130 FL: 1-atgctgcggctgctgctgagacaccacttccactgcctgctgctgtgtgccgtgtgggccaccc cttgtctggccagcccttggagcaccctgaccgccaaccagaaccctagccccccttggtccaa gctgacctacagcaagccccacgacgccgccaccttctactgcccctttctgtaccccagccct cccagaagccccctgcagttcagcggcttccagagagtgtccaccggccctgagtgccggaacg agacactgtacctgctgtacaaccgggagggccagacactggtggagcggagcagcacctgggt gaaaaaagtgatctggtatctgagcggccggaaccagaccatcctgcagcggatgcccagaacc gccagcaagcccagcgacggcaacgtgcagatcagcgtggaggacgccaaaatcttcggcgccc acatggtgcccaagcagaccaagctgctgagattcgtggtcaacgacggcaccagatatcagat gtgcgtgatgaagctggaaagctgggcccacgtgttccgggactactccgtgagcttccaggtc cggctgaccttcaccgaggccaacaaccagacctacaccttctgcacccaccccaacctgatcg tgtgataa - 648 UL130FL CMV; MLRLLLRHHFHCLLLCAVWATPCLASPWSTLTANQNPSPPWSKLTYSKPHDAATFYCPF LYPSPPRSPLQFSGFQRVSTGPECRNETLYLLYNREGQTLVERSSTWVKKVIWYLSGRN QTILQRMPRTASKPSDGNVQISVEDAKIFGAHMVPKQTKLLRFVVNDGTRYQMCVMKLE SWAHVFRDYSVSFQVRLTFTEANNQTYTFCTHPNLIV-- CMV UL131 FL: 1-atgcggctgtgcagagtgtggctgtccgtgtgcctgtgtgccgtggtgctgggccagtgccaga gagagacagccgagaagaacgactactaccgggtgccccactactgggatgcctgcagcagagc cctgcccgaccagacccggtacaaatacgtggagcagctcgtggacctgaccctgaactaccac tacgacgccagccacggcctggacaacttcgacgtgctgaagcggatcaacgtgaccgaggtgt ccctgctgatcagcgacttccggcggcagaacagaagaggcggcaccaacaagcggaccacctt caacgccgctggctctctggcccctcacgccagatccctggaattcagcgtgcggctgttcgcc aactgataa - 393 CMV UL131 FL; MRLCRVWLSVCLCAVVLGQCQRETAEKNDYYRVPHYWDACSRALPDQTRYKYVEQLVDL TLNYHYDASHGLDNFDVLKRINVTEVSLLISDFRRQNRRGGTNKRTTFNAAGSLAPHAR SLEFSVRLFAN; aacgttactggccgaagccgcttggaataaggccggtgtgcgtttgtctatatgttattttcca ccatattgccgtcttttggcaatgtgagggcccggaaacctggccctgtcttcttgacgagcat tcctaggggtctttcccctctcgccaaaggaatgcaaggtctgttgaatgtcgtgaaggaagca gttcctctggaagcttcttgaagacaaacaacgtctgtagcgaccctttgcaggcagcggaacc ccccacctggcgacaggtgcctctgcggccaaaagccacgtgtataagatacacctgcaaaggc ggcacaaccccagtgccacgttgtgagttggatagttgtggaaagagtcaaatggctctcctca agcgtattcaacaaggggctgaaggatgcccagaaggtaccccattgtatgggatctgatctgg ggcctcggtgcacatgctttacatgtgtttagtcgaggttaaaaaaacgtctaggccccccgaa ccacggggacgtggttttcctttgaaaaacacgataat nucleotide sequence EV71 IRES; gtacctttgtacgcctgttttataccccctccctgatttgcaacttagaagcaa cgcaaaccagatcaatagtaggtgtgacataccagtcgcatcttgatcaagcacttctg tatccccggaccgagtatcaatagactgtgcacacggttgaaggagaaaacgtccgtta cccggctaactacttcgagaagcctagtaacgccattgaagttgcagagtgtttcgctc agcactccccccgtgtagatcaggtcgatgagtcaccgcattccccacgggcgaccgtg gcggtggctgcgttggcggcctgcctatggggtaacccataggacgctctaatacggac atggcgtgaagagtctattgagctagttagtagtcctccggcccctgaatgcggctaat cctaactgcggagcacatacccttaatccaaagggcagtgtgtcgtaacgggcaactct gcagcggaaccgactactttgggtgtccgtgtttctttttattcttgtattggctgctt atggtgacaattaaagaattgttaccatatagctattggattggccatccagtgtcaaa cagagctattgtatatctctttgttggattcacacctctcactcttgaaacgttacaca ccctcaattacattatactgctgaacacgaagcg subgenomic promoter VEE5' CTCTCTACGGCTAACCTGAATGGA-3 'modified vector PVCR sun gH-gL SGP cgcgtcggctacaattaatacataaccttatgtatcatacacatacgatttaggtgacactata gatgggcggcgcatgagagaagcccagaccaattacctacccaaaatggagaaagttcacgttg acatcgaggaagacagcccattcctcagagctttgcagcggagcttcccgcagtttgaggtaga agccaagcaggtcactgataa tgaccatgctaatgccagagcgttttcgcatctggcttcaaaa ctgatcgaaacggaggtggacccatccgacacgatccttgacattggaagtgcgcccgcccgca gaatgtattctaagcacaagtatcattgtatctgtccgatgagatgtgcggaagatccggacag attgtataagtatgcaactaagctgaagaaaaactgtaaggaaataactgataaggaattggac aagaaaatgaaggagctcgccgccgtcatgagcgaccctgacctggaaactgagactatgtgcc tccacgacgacgagtcgtgtcgctacgaagggcaagtcgctgtttaccaggatgtatacgcggt tgacggaccgacaagtctctatcaccaagccaataagggagttagagtcgcctactggataggc tttgacaccaccccttttatgtttaagaacttggctggagcatatccatcatactctaccaact gggccgacgaaaccgtgttaacggctcgtaacataggcctatgcagctctgacgttatggagcg gtcacgtagagggatgtccattcttagaaagaagtatttgaaaccatccaacaatgttctattc tctgttggctcgaccatctaccacgagaagagggacttactgaggagctggcacctgccgtctg tatttcacttacgtggcaagcaaaattacacatgtcggtgtgagactatagttagttgcgacgg gtacgtcgttaaaagaatagctatcagtccaggcctgtatgggaagccttcaggctatgctgct acgatgcaccgcgagggattcttgtgctgcaaagtgacagacacattgaacggggagagggtct cttttcccgtgtgcacgtatgtgccagctacattgtgtgaccaaatgactggcatactggcaac agatgtcagtgcggacgacgcgcaaaaactgctggttgggctcaac cagcgtatagtcgtcaac ggtcgcacccagagaaacaccaataccatgaaaaattaccttttgcccgtagtggcccaggcat ttgctaggtgggcaaaggaatataaggaagatcaagaagatgaaaggccactaggactacgaga tagacagttagtcatggggtgttgttgggcttttagaaggcacaagataacatctatttataag cgcccggatacccaaaccatcatcaaagtgaacagcgatttccactcattcgtgctgcccagga taggcagtaacacattggagatcgggctgagaacaagaatcaggaaaatgttagaggagcacaa ggagccgtcacctctcattaccgccgaggacgtacaagaagctaagtgcgcagccgatgaggct aaggaggtgcgtgaagccgaggagttgcgcgcagctctaccacctttggcagctgatgttgagg agcccactctggaagccgatgtagacttgatgttacaagaggctggggccggctcagtggagac acctcgtggcttgataaaggttaccagctacgctggcgaggacaagatcggctcttacgctgtg ctttctccgcaggctgtactcaagagtgaaaaattatcttgcatccaccctctcgctgaacaag tcatagtgataacacactctggccgaaaagggcgttatgccgtggaaccataccatggtaaagt agtggtgccagagggacatgcaatacccgtccaggactttcaagctctgagtgaaagtgccacc attgtgtacaacgaacgtgagttcgtaaacaggtacctgcaccatattgccacacatggaggag cgctgaacactgatgaagaatattacaaaactgtcaagcccagcgagcacgacggcgaatacct gtacgacatcgacaggaaacagtgcgtcaagaaagaactagtcactgggctagggctcacaggc gagctg gtggatcctcccttccatgaattcgcctacgagagtctgagaacacgaccagccgctc cttaccaagtaccaaccataggggtgtatggcgtgccaggatcaggcaagtctggcatcattaa aagcgcagtcaccaaaaaagatctagtggtgagcgccaagaaagaaaactgtgcagaaattata agggacgtcaagaaaatgaaagggctggacgtcaatgccagaactgtggactcagtgctcttga atggatgcaaacaccccgtagagaccctgtatattgacgaagcttttgcttgtcatgcaggtac tctcagagcgctcatagccattataagacctaaaaaggcagtgctctgcggggatcccaaacag tgcggtttttttaacatgatgtgcctgaaagtgcattttaaccacgagatttgcacacaagtct tccacaaaagcatctctcgccgttgcactaaatctgtgacttcggtcgtctcaaccttgtttta cgacaaaaaaatgagaacgacgaatccgaaagagactaagattgtgattgacactaccggcagt accaaacctaagcaggacgatctcattctcacttgtttcagagggtgggtgaagcagttgcaaa tagattacaaaggcaacgaaataatgacggcagctgcctctcaagggctgacccgtaaaggtgt gtatgccgttcggtacaaggtgaatgaaaatcctctgtacgcacccacctcagaacatgtgaac gtcctactgacccgcacggaggaccgcatcgtgtggaaaacactagccggcgacccatggataa aaacactgactgccaagtaccctgggaatttcactgccacgatagaggagtggcaagcagagca tgatgccatcatgaggcacatcttggagagaccggaccctaccgacgtcttccagaataaggca aacgtgtgttgggccaaggctttagtgccgg tgctgaagaccgctggcatagacatgaccactg aacaatggaacactgtggattattttgaaacggacaaagctcactcagcagagatagtattgaa ccaactatgcgtgaggttctttggactcgatctggactccggtctattttctgcacccactgtt ccgttatccattaggaataatcactgggataactccccgtcgcctaacatgtacgggctgaata aagaagtggtccgtcagctctctcgcaggtacccacaactgcctcgggcagttgccactggaag agtctatgacatgaacactggtacactgcgcaattatgatccgcgcataaacctagtacctgta aacagaagactgcctcatgctttagtcctccaccataatgaacacccacagagtgacttttctt cattcgtcagcaaattgaagggcagaactgtcctggtggtcggggaaaagttgtccgtcccagg caaaatggttgactggttgtcagaccggcctgaggctaccttcagagctcggctggatttaggc atcccaggtgatgtgcccaaatatgacataatatttgttaatgtgaggaccccatataaatacc atcactatcagcagtgtgaagaccatgccattaagcttagcatgttgaccaagaaagcttgtct gcatctgaatcccggcggaacctgtgtcagcataggttatggttacgctgacagggccagcgaa agcatcattggtgctatagcgcggcagttcaagttttcccgggtatgcaaaccgaaatcctcac ttgaagagacggaagttctgtttgtattcattgggtacgatcgcaaggcccgtacgcacaatcc ttacaagctttcatcaaccttgaccaacatttatacaggttccagactccacgaagccggatgt gcaccctcatatcatgtggtgcgaggggatattgccacggccaccgaaggagtgat tataaatg ctgctaacagcaaaggacaacctggcggaggggtgtgcggagcgctgtataagaaattcccgga aagcttcgatttacagccgatcgaagtaggaaaagcgcgactggtcaaaggtgcagctaaacat atcattcatgccgtaggaccaaacttcaacaaagtttcggaggttgaaggtgacaaacagttgg cagaggcttatgagtccatcgctaagattgtcaacgataacaattacaagtcagtagcgattcc actgttgtccaccggcatcttttccgggaacaaagatcgactaacccaatcattgaaccatttg ctgacagctttagacaccactgatgcagatgtagccatatactgcagggacaagaaatgggaaa tgactctcaaggaagcagtggctaggagagaagcagtggaggagatatgcatatccgacgactc ttcagtgacagaacctgatgcagagctggtgagggtgcatccgaagagttctttggctggaagg aagggctacagcacaagcgatggcaaaactttctcatatttggaagggaccaagtttcaccagg cggccaaggatatagcagaaattaatgccatgtggcccgttgcaacggaggccaatgagcaggt atgcatgtatatcctcggagaaagcatgagcagtattaggtcgaaatgccccgtcgaagagtcg gaagcctcctcaccacctagcacgctgccttgcttgtgcatccatgccatgactccagaaagag tacagcgcctaaaagcctcacgtccagaacaaattactgtgtgctcatcctttccattgccgaa gtatagaatcactggtgtgcagaagatccaatgctcccagcctatattgttctcaccgaaagtg cctgcgtatattcatccaaggaagtatctcgtggaaacaccaccggtagacgagactccggagc catcggcagagaacca atccacagaggggacacctgaacaaccaccacttataaccgaggatga gaccaggactagaacgcctgagccgatcatcatcgaagaggaagaagaggatagcataagtttg ctgtcagatggcccgacccaccaggtgctgcaagtcgaggcagacattcacgggccgccctctg tatctagctcatcctggtccattcctcatgcatccgactttgatgtggacagtttatccatact tgacaccctggagggagctagcgtgaccagcggggcaacgtcagccgagactaactcttacttc gcaaagagtatggagtttctggcgcgaccggtgcctgcgcctcgaacagtattcaggaaccctc cacatcccgctccgcgcacaagaacaccgtcacttgcacccagcagggcctgctcgagagggat cacgggagaaaccgtgggatacgcggttacacacaatagcgagggcttcttgctatgcaaagtt actgacacagtaaaaggagaacgggtatcgttccctgtgtgcacgtacatcccggccaccataa actcgagaaccagcctggtctccaacccgccaggcgtaaatagggtgattacaagagaggagtt tgaggcgttcgtagcacaacaacaatgacggtttgatgcgggtgcatacatcttttcctccgac accggtcaagggcatttacaacaaaaatcagtaaggcaaacggtgctatccgaagtggtgttgg agaggaccgaattggagatttcgtatgccccgcgcctcgaccaagaaaaagaagaattactacg caagaaattacagttaaatcccacacctgctaacagaagcagataccagtccaggaaggtggag aacatgaaagccataacagctagacgtattctgcaaggcctagggcattatttgaaggcagaag gaaaagtggagtgctaccgaaccctgcatcctgttcctttg tattcatctagtgtgaaccgtgc gtggcttcttactgtattattccagagtacgatgcctatttggacatggttgacggagcttcat gctgcttagacactgccagtttttgccctgcaaagctgcgcagctttccaaagaaacactccta tttggaacccacaatacgatcggcagtgccttcagcgatccagaacacgctccagaacgtcctg cttttcaagccccaaggtcgcagtggaagcctgtaacgccatgttgaaagagaactttccgact gcagctgccacaaaaagaaattgcaatgtcacgcaaatgagagaattgcccgtattggattcgg cggcctttaatgtggaatgcttcaagaaatatgcgtgtaataatgaatattgggaaacgtttaa agaaaaccccatcaggcttactgaagaaaacgtggtaaattacattaccaaattaaaaggacca aaagctgctgctctttttgcgaagacacataatttgaatatgttgcaggacataccaatggaca ggtttgtaatggacttaaagagagacgtgaaagtgactccaggaacaaaacatactgaagaacg gcccaaggtacaggtgatccaggctgccgatccgctagcaacagcgtatctgtgcggaatccac cgagagctggttaggagattaaatgcggtcctgcttccgaacattcatacactgtttgatatgt cggctgaagactttgacgctattatagccgagcacttccagcctggggattgtgttctggaaac tgacatcgcgtcgtttgataaaagtgaggacgacgccatggctctgaccgcgttaatgattctg gaagacttaggtgtggacgcagagctgttgacgctgattgaggcggctttcggcgaaatttcat c caatacatttgcccactaaaactaaatttaaattcggagccatgatgaaatctggaatgttcct acactgtttgtgaacacagtcattaacattgtaatcgcaagcagagtgttgagagaacggcta accggatcaccatgtgcagcattcattggagatgacaatatcgtgaaaggagtcaaatcggaca aattaatggcagacaggtgcgccacctggttgaatatggaagtcaagattatagatgctgtggt gggcgagaaagcgccttatttctgtggagggtttattttgtgtgactccgtgaccggcacagcg tgccgtgtggcagaccccctaaaaaggctgtttaagcttggcaaacctctggcagcagacgatg aacatgatgatgacaggagaagggcattgcatgaagagtcaacacgctggaaccgagtgggtat tctttcagagctgtgcaaggcagtagaatcaaggtatgaaaccgtaggaacttccatcatagtt atggccatgactactctagctagcagtgttaaatcattcagctacctgagaggggcccctataa ctctctacggctaacctgaatggactacgacatagtctagtcgacgccaccatgaggcctggcc tgccctcctacctgatcatcctggccgtgtgcctgttcagccacctgctgtccagcagatacgg cgccgaggccgtgagcgagcccctggacaaggctttccacctgctgctgaacacctacggcaga cccatccggtttctgcgggagaacaccacccagtgcacctacaacagcagcctgcggaacagca ccgtcgtgagagagaacgccatcagcttcaactttttccagagctacaaccagtactacgtgtt ccacatgcccagatgcctgtttgccggccctctggccgagcagttcctgaaccaggtggacctg accgagacactggaaagataccagcagcggctgaatacctacgccctggtgtccaaggacctgg ccagctaccggtcctttagccagcag ctcaaggctcaggatagcctcggcgagcagcctaccac cgtgccccctcccatcgacctgagcatcccccacgtgtggatgcctccccagaccacccctcac ggctggaccgagagccacaccacctccggcctgcacagaccccacttcaaccagacctgcatcc tgttcgacggccacgacctgctgtttagcaccgtgaccccctgcctgcaccagggcttctacct gatcgacgagctgagatacgtgaagatcaccctgaccgaggatttcttcgtggtcaccgtgtcc atcgacgacgacacccccatgctgctgatcttcggccacctgcccagagtgctgttcaaggccc cctaccagcgggacaacttcatcctgcggcagaccgagaagcacgagctgctggtgctggtcaa gaaggaccagctgaaccggcactcctacctgaaggaccccgacttcctggacgccgccctggac ttcaactacctggacctgagcgccctgctgagaaacagcttccacagatacgccgtggacgtgc tgaagtccggacggtgccagatgctcgatcggcggaccgtggagatggccttcgcctatgccct cgccctgttcgccgctgccagacaggaagaggctggcgcccaggtgtcagtgcccagagccctg gatagacaggccgccctgctgcagatccaggaattcatgatcacctgcctgagccagacccccc ctagaaccaccctgctgctgtaccccacagccgtggatctggccaagagggccctgtggacccc caaccagatcaccgacatcacaagcctcgtgcggctcgtgtacatcctgagcaagcagaaccag cagcacctgatcccccagtgggccctgagacagatcgccgacttcgccctgaagctgcacaaga cccatctggccagctttctgagcgccttcgccaggcaggaactgtacctga tgggcagcctggt ccacagcatgctggtgcataccaccgagcggcgggagatcttcatcgtggagacaggcctgtgt agcctggccgagctgtcccactttacccagctgctggcccaccctcaccacgagtacctgagcg acctgtacaccccctgcagcagcagcggcagacgggaccacagcctggaacggctgaccagact gttccccgatgccaccgtgcctgctacagtgcctgccgccctgtccatcctgtccaccatgcag cccagcaccctggaaaccttccccgacctgttctgcctgcccctgggcgagagctttagcgccc tgaccgtgtccgagcacgtgtcctacatcgtgaccaatcagtacctgatcaagggcatcagcta ccccgtgtccaccacagtcgtgggccagagcctgatcatcacccagaccgacagccagaccaag tgcgagctgacccggaacatgcacaccacacacagcatcaccgtggccctgaacatcagcctgg aaaactgcgctttctgtcagtctgccctgctggaatacgacgatacccagggcgtgatcaacat catgtacatgcacgacagcgacgacgtgctgttcgccctggacccctacaacgaggtggtggtg tccagcccccggacccactacctgatgctgctgaagaacggcaccgtgctggaagtgaccgacg tggtggtggacgccaccgactgataatctagacggcgcgcccacccagcggccgcctataactc tctacggctaacctgaatggactacgacatagtctagtcgacgccaccatgtgcagaaggcccg actgcggcttcagcttcagccctggacccgtgatcctgctgtggtgctgcctgctgctgcctat cgtgtcctctgccgccgtgtctgtggcccctacagccgccgagaaggtgccagccgagtgcccc gagctgaccag aagatgcctgctgggcgaggtgttcgagggcgacaagtacgagagctggctgc ggcccctggtcaacgtgaccggcagagatggccccctgagccagctgatccggtacagacccgt gacccccgaggccgccaatagcgtgctgctggacgaggccttcctggataccctggccctgctg tacaacaaccccgaccagctgagagccctgctgaccctgctgtccagcgacaccgcccccagat ggatgaccgtgatgcggggctacagcgagtgtggagatggcagccctgccgtgtacacctgcgt ggacgacctgtgcagaggctacgacctgaccagactgagctacggccggtccatcttcacagag cacgtgctgggcttcgagctggtgccccccagcctgttcaacgtggtggtggccatccggaacg aggccaccagaaccaacagagccgtgcggctgcctgtgtctacagccgctgcacctgagggcat cacactgttctacggcctgtacaacgccgtgaaagagttctgcctccggcaccagctggatccc cccctgctgagacacctggacaagtactacgccggcctgcccccagagctgaagcagaccagag tgaacctgcccgcccacagcagatatggccctcaggccgtggacgccagatgataatctagacg gcgcgcccacccaatcgatgtacttccgaggaactcacgtgcataatgcatcaggctggtacat tagatccccgcttaccgcgggcaatatagcaacactaaaaactcgatgtacttccgaggaagcg cagtgcataatgctgcgcagtgttgccacataaccactatattaaccatttatctagcggacgc caaaaactcaatgtatttctgaggaagcgtggtgcataatgccacgcagcgtctgcataacttt tattatttcttttattaatcaacaaaattttgtttt taacatttcaaaaaaaaaaaaaaaaaaa aaaaaaaaaaaaaaaaaaaaagggtcggcatggcatctccacctcctcgcggtccgacctgggc atccgaaggaggacgcacgtccactcggatggctaagggagagccacgagctcctgtttaaacc agctccaattcgccctatagtgagtcgtattacgcgcgctcactggccgtcgttttacaacgtc gtgactgggaaaaccctggcgttacccaacttaatcgccttgcagcacatccccctttcgccag ctggcgtaatagcgaagaggcccgcaccgatcgcccttcccaacagttgcgcagcctgaatggc gaatgggacgcgccctgtagcggcgcattaagcgcggcgggtgtggtggttacgcgcagcgtga ccgctacacttgccagcgccctagcgcccgctcctttcgctttcttcccttcctttctcgccac gttcgccggctttccccgtcaagctctaaatcgggggctccctttagggttccgatttagtgct ttacggcacctcgaccccaaaaaacttgattagggtgatggttcacgtagtgggccatcgccct gatagacggtttttcgccctttgacgttggagtccacgttctttaatagtggactcttgttcca aactggaacaacactcaaccctatctcggtctattcttttgatttataagggattttgccgatt tcggcctattggttaaaaaatgagctgatttaacaaaaatttaacgcgaattttaacaaaatat taacgcttacaatttaggtggcacttttcggggaaatgtgcgcggaacccctatttgtttattt ttctaaatacattcaaatatgtatccgctcatgagacaataaccctgataaatgcttcaataat attgaaaaaggaagagtatgagtattcaacatttccgtgtcgcccttattcccttttttgc ggc attttgccttcctgtttttgctcacccagaaacgctggtgaaagtaaaagatgctgaagatcag ttgggtgcacgagtgggttacatcgaactggatctcaacagcggtaagatccttgagagttttc gccccgaagaacgttttccaatgatgagcacttttaaagttctgctatgtggcgcggtattatc ccgtattgacgccgggcaagagcaactcggtcgccgcatacactattctcagaatgacttggtt gagtactcaccagtcacagaaaagcatcttacggatggcatgacagtaagagaattatgcagtg ctgccataaccatgagtgataacactgcggccaacttacttctgacaacgatcggaggaccgaa ggagctaaccgcttttttgcacaacatgggggatcatgtaactcgccttgatcgttgggaaccg gagctgaatgaagccataccaaacgacgagcgtgacaccacgatgcctgtagcaatggcaacaa cgttgcgcaaactattaactggcgaactacttactctagcttcccggcaacaattaatagactg gatggaggcggataaagttgcaggaccacttctgcgctcggcccttccggctggctggtttatt gctgataaatctggagccggtgagcgtgggtctcgcggtatcattgcagcactggggccagatg gtaagccctcccgtatcgtagttatctacacgacggggagtcaggcaactatggatgaacgaaa tagacagatcgctgagataggtgcctcactgattaagcattggtaactgtcagaccaagtttac tcatatatactttagattgatttaaaacttcatttttaatttaaaaggatctaggtgaagatcc tttttgataatctcatgaccaaaatcccttaacgtgagttttcgttccactgagcgtcagaccc cgtagaaaagatcaaaggatc ttcttgagatcctttttttctgcgcgtaatctgctgcttgcaa acaaaaaaaccaccgctaccagcggtggtttgtttgccggatcaagagctaccaactctttttc cgaaggtaactggcttcagcagagcgcagataccaaatactgttcttctagtgtagccgtagtt aggccaccacttcaagaactctgtagcaccgcctacatacctcgctctgctaatcctgttacca gtggctgctgccagtggcgataagtcgtgtcttaccgggttggactcaagacgatagttaccgg ataaggcgcagcggtcgggctgaacggggggttcgtgcacacagcccagcttggagcgaacgac ctacaccgaactgagatacctacagcgtgagctatgagaaagcgccacgcttcccgaagggaga aaggcggacaggtatccggtaagcggcagggtcggaacaggagagcgcacgagggagcttccag ggggaaacgcctggtatctttatagtcctgtcgggtttcgccacctctgacttgagcgtcgatt tttgtgatgctcgtcaggggggcggagcctatggaaaaacgccagcaacgcggcctttttacgg ttcctggccttttgctggccttttgctcacatgttctttcctgcgttatcccctgattctgtgg ataaccgtattaccgcctttgagtgagctgataccgctcgccgcagccgaacgaccgagcgcag cgagtcagtgagcgaggaagcggaagagcgcccaatacgcaaaccgcctctccccgcgcgttgg ccgattcattaatgcagctggcacgacaggtttcccgactggaaagcgggcagtgagcgcaacg caattaatgtgagttagctcactcattaggcaccccaggctttacactttatgctcccggctcg tatgttgtgtggaattgtgagcggataacaatttcacacaggaaac agctatgaccatgattac modified vector gccaagcgcgcaattaaccctcactaaagggaacaaaagctgggtaccggcgcca PVCR FL-SGP gH gL cgcgtcggctacaattaatacataaccttatgtatcatacacatacgatttaggtgacactata gatgggcggcgcatgagagaagcccagaccaattacctacccaaaatggagaaagttcacgttg acatcgaggaagacagcccattcctcagagctttgcagcggagcttcccgcagtttgaggtaga agccaagcaggtcactgataatgaccatgctaatgccagagcgttttcgcatctggcttcaaaa ctgatcgaaacggaggtggacccatccgacacgatccttgacattggaagtgcgcccgcccgca gaatgtattctaagcacaagtatcattgtatctgtccgatgagatgtgcggaagatccggacag attgtataagtatgcaactaagctgaagaaaaactgtaaggaaataactgataaggaattggac aagaaaatgaaggagctcgccgccgtcatgagcgaccctgacctggaaactgagactatgtgcc tccacgacgacgagtcgtgtcgctacgaagggcaagtcgctgtttaccaggatgtatacgcggt tgacggaccgacaagtctctatcaccaagccaataagggagttagagtcgcctactggataggc tttgacaccaccccttttatgtttaagaacttggctggagcatatccatcatactctaccaact gggccgacgaaaccgtgttaacggctcgtaacataggcctatgcagctctgacgttatggagcg gtcacgtagagggatgtccattcttagaaagaagtatttgaaaccatccaacaatgttctattc tctgttggctcgaccatctaccacgagaagagggacttactg aggagctggcacctgccgtctg gtacgtcgttaaaagaatagctatcagtccaggcctgtatgggaagccttcaggctatgctgct acgatgcaccgcgagggattcttgtgctgcaaagtgacagacacattgaacggggagagggtct cttttcccgtgtgcacgtatgtgccagctacattgtgtgaccaaatgactggcatactggcaac tatttcacttacgtggcaagcaaaattacacatgtcggtgtgagactatagttagttgcgacgg agatgtcagtgcggacgacgcgcaaaaactgctggttgggctcaaccagcgtatagtcgtcaac ggtcgcacccagagaaacaccaataccatgaaaaattaccttttgcccgtagtggcccaggcat ttgctaggtgggcaaaggaatataaggaagatcaagaagatgaaaggccactaggactacgaga tagacagttagtcatggggtgttgttgggcttttagaaggcacaagataacatctatttataag cgcccggatacccaaaccatcatcaaagtgaacagcgatttccactcattcgtgctgcccagga taggcagtaacacattggagatcgggctgagaacaagaatcaggaaaatgttagaggagcacaa ggagccgtcacctctcattaccgccgaggacgtacaagaagctaagtgcgcagccgatgaggct aaggaggtgcgtgaagccgaggagttgcgcgcagctctaccacctttggcagctgatgttgagg agcccactctggaagccgatgtagacttgatgttacaagaggctggggccggctcagtggagac acctcgtggcttgataaaggttaccagctacgctggcgaggacaagatcggctcttacgctgtg ctttctccgcaggctgtactcaagagtgaaaaattatcttgcatccaccctctcgctgaacaag tc atagtgataacacactctggccgaaaagggcgttatgccgtggaaccataccatggtaaagt agtggtgccagagggacatgcaatacccgtccaggactttcaagctctgagtgaaagtgccacc attgtgtacaacgaacgtgagttcgtaaacaggtacctgcaccatattgccacacatggaggag cgctgaacactgatgaagaatattacaaaactgtcaagcccagcgagcacgacggcgaatacct gtacgacatcgacaggaaacagtgcgtcaagaaagaactagtcactgggctagggctcacaggc gagctggtggatcctcccttccatgaattcgcctacgagagtctgagaacacgaccagccgctc cttaccaagtaccaaccataggggtgtatggcgtgccaggatcaggcaagtctggcatcattaa aagcgcagtcaccaaaaaagatctagtggtgagcgccaagaaagaaaactgtgcagaaattata agggacgtcaagaaaatgaaagggctggacgtcaatgccagaactgtggactcagtgctcttga atggatgcaaacaccccgtagagaccctgtatattgacgaagcttttgcttgtcatgcaggtac tctcagagcgctcatagccattataagacctaaaaaggcagtgctctgcggggatcccaaacag tgcggtttttttaacatgatgtgcctgaaagtgcattttaaccacgagatttgcacacaagtct tccacaaaagcatctctcgccgttgcactaaatctgtgacttcggtcgtctcaaccttgtttta cgacaaaaaaatgagaacgacgaatccgaaagagactaagattgtgattgacactaccggcagt accaaacctaagcaggacgatctcattctcacttgtttcagagggtgggtgaagcagttgcaaa tagattacaaaggcaacgaaataatga cggcagctgcctctcaagggctgacccgtaaaggtgt gtatgccgttcggtacaaggtgaatgaaaatcctctgtacgcacccacctcagaacatgtgaac gtcctactgacccgcacggaggaccgcatcgtgtggaaaacactagccggcgacccatggataa aaacactgactgccaagtaccctgggaatttcactgccacgatagaggagtggcaagcagagca tgatgccatcatgaggcacatcttggagagaccggaccctaccgacgtcttccagaataaggca aacgtgtgttgggccaaggctttagtgccggtgctgaagaccgctggcatagacatgaccactg aacaatggaacactgtggattattttgaaacggacaaagctcactcagcagagatagtattgaa ccaactatgcgtgaggttctttggactcgatctggactccggtctattttctgcacccactgtt ccgttatccattaggaataatcactgggataactccccgtcgcctaacatgtacgggctgaata aagaagtggtccgtcagctctctcgcaggtacccacaactgcctcgggcagttgccactggaag agtctatgacatgaacactggtacactgcgcaattatgatccgcgcataaacctagtacctgta aacagaagactgcctcatgctttagtcctccaccataatgaacacccacagagtgacttttctt cattcgtcagcaaattgaagggcagaactgtcctggtggtcggggaaaagttgtccgtcccagg caaaatggttgactggttgtcagaccggcctgaggctaccttcagagctcggctggatttaggc atcccaggtgatgtgcccaaatatgacataatatttgttaatgtgaggaccccatataaatacc atcactatcagcagtgtgaagaccatgccattaagcttagcatgttgaccaa gaaagcttgtct gcatctgaatcccggcggaacctgtgtcagcataggttatggttacgctgacagggccagcgaa agcatcattggtgctatagcgcggcagttcaagttttcccgggtatgcaaaccgaaatcctcac ttgaagagacggaagttctgtttgtattcattgggtacgatcgcaaggcccgtacgcacaatcc ttacaagctttcatcaaccttgaccaacatttatacaggttccagactccacgaagccggatgt gcaccctcatatcatgtggtgcgaggggatattgccacggccaccgaaggagtgattataaatg ctgctaacagcaaaggacaacctggcggaggggtgtgcggagcgctgtataagaaattcccgga aagcttcgatttacagccgatcgaagtaggaaaagcgcgactggtcaaaggtgcagctaaacat atcattcatgccgtaggaccaaacttcaacaaagtttcggaggttgaaggtgacaaacagttgg cagaggcttatgagtccatcgctaagattgtcaacgataacaattacaagtcagtagcgattcc actgttgtccaccggcatcttttccgggaacaaagatcgactaacccaatcattgaaccatttg ctgacagctttagacaccactgatgcagatgtagccatatactgcagggacaagaaatgggaaa tgactctcaaggaagcagtggctaggagagaagcagtggaggagatatgcatatccgacgactc ttcagtgacagaacctgatgcagagctggtgagggtgcatccgaagagttctttggctggaagg aagggctacagcacaagcgatggcaaaactttctcatatttggaagggaccaagtttcaccagg cggccaaggatatagcagaaattaatgccatgtggcccgttgcaacggaggccaatgagcaggt atgcatgtatat cctcggagaaagcatgagcagtattaggtcgaaatgccccgtcgaagagtcg gaagcctcctcaccacctagcacgctgccttgcttgtgcatccatgccatgactccagaaagag tacagcgcctaaaagcctcacgtccagaacaaattactgtgtgctcatcctttccattgccgaa gtatagaatcactggtgtgcagaagatccaatgctcccagcctatattgttctcaccgaaagtg cctgcgtatattcatccaaggaagtatctcgtggaaacaccaccggtagacgagactccggagc catcggcagagaaccaatccacagaggggacacctgaacaaccaccacttataaccgaggatga gaccaggactagaacgcctgagccgatcatcatcgaagaggaagaagaggatagcataagtttg ctgtcagatggcccgacccaccaggtgctgcaagtcgaggcagacattcacgggccgccctctg tatctagctcatcctggtccattcctcatgcatccgactttgatgtggacagtttatccatact tgacaccctggagggagctagcgtgaccagcggggcaacgtcagccgagactaactcttacttc gcaaagagtatggagtttctggcgcgaccggtgcctgcgcctcgaacagtattcaggaaccctc cacatcccgctccgcgcacaagaacaccgtcacttgcacccagcagggcctgctcgagagggat cacgggagaaaccgtgggatacgcggttacacacaatagcgagggcttcttgctatgcaaagtt actgacacagtaaaaggagaacgggtatcgttccctgtgtgcacgtacatcccggccaccataa actcgagaaccagcctggtctccaacccgccaggcgtaaatagggtgattacaagagaggagtt tgaggcgttcgtagcacaacaacaatgacggtttgat gcgggtgcatacatcttttcctccgac accggtcaagggcatttacaacaaaaatcagtaaggcaaacggtgctatccgaagtggtgttgg agaggaccgaattggagatttcgtatgccccgcgcctcgaccaagaaaaagaagaattactacg caagaaattacagttaaatcccacacctgctaacagaagcagataccagtccaggaaggtggag aacatgaaagccataacagctagacgtattctgcaaggcctagggcattatttgaaggcagaag gaaaagtggagtgctaccgaaccctgcatcctgttcctttgtattcatctagtgtgaaccgtgc cttttcaagccccaaggtcgcagtggaagcctgtaacgccatgttgaaagagaactttccgact gtggcttcttactgtattattccagagtacgatgcctatttggacatggttgacggagcttcat gctgcttagacactgccagtttttgccctgcaaagctgcgcagctttccaaagaaacactccta tttggaacccacaatacgatcggcagtgccttcagcgatccagaacacgctccagaacgtcctg gcagctgccacaaaaagaaattgcaatgtcacgcaaatgagagaattgcccgtattggattcgg cggcctttaatgtggaatgcttcaagaaatatgcgtgtaataatgaatattgggaaacgtttaa agaaaaccccatcaggcttactgaagaaaacgtggtaaattacattaccaaattaaaaggacca aaagctgctgctctttttgcgaagacacataatttgaatatgttgcaggacataccaatggaca ggtttgtaatggacttaaagagagacgtgaaagtgactccaggaacaaaacatactgaagaacg gcccaaggtacaggtgatccaggctgccgatccgctagcaacagcgtatctgtgcggaatcc ac cgagagctggttaggagattaaatgcggtcctgcttccgaacattcatacactgtttgatatgt cggctgaagactttgacgctattatagccgagcacttccagcctggggattgtgttctggaaac tgacatcgcgtcgtttgataaaagtgaggacgacgccatggctctgaccgcgttaatgattctg gaagacttaggtgtggacgcagagctgttgacgctgattgaggcggctttcggcgaaatttcat caatacatttgcccactaaaactaaatttaaattcggagccatgatgaaatctggaatgttcct cacactgtttgtgaacacagtcattaacattgtaatcgcaagcagagtgttgagagaacggcta accggatcaccatgtgcagcattcattggagatgacaatatcgtgaaaggagtcaaatcggaca aattaatggcagacaggtgcgccacctggttgaatatggaagtcaagattatagatgctgtggt gggcgagaaagcgccttatttctgtggagggtttattttgtgtgactccgtgaccggcacagcg tgccgtgtggcagaccccctaaaaaggctgtttaagcttggcaaacctctggcagcagacgatg aacatgatgatgacaggagaagggcattgcatgaagagtcaacacgctggaaccgagtgggtat tctttcagagctgtgcaaggcagtagaatcaaggtatgaaaccgtaggaacttccatcatagtt atggccatgactactctagctagcagtgttaaatcattcagctacctgagaggggcccctataa ctctctacggctaacctgaatggactacgacatagtctagtcgacgccaccatgaggcctggcc tgccctcctacctgatcatcctggccgtgtgcctgttcagccacctgctgtccagcagatacgg cgccgaggccgtgagcgagccc ctggacaaggctttccacctgctgctgaacacctacggcaga cccatccggtttctgcgggagaacaccacccagtgcacctacaacagcagcctgcggaacagca ccgtcgtgagagagaacgccatcagcttcaactttttccagagctacaaccagtactacgtgtt ccacatgcccagatgcctgtttgccggccctctggccgagcagttcctgaaccaggtggacctg accgagacactggaaagataccagcagcggctgaatacctacgccctggtgtccaaggacctgg ccagctaccggtcctttagccagcagctcaaggctcaggatagcctcggcgagcagcctaccac cgtgccccctcccatcgacctgagcatcccccacgtgtggatgcctccccagaccacccctcac ggctggaccgagagccacaccacctccggcctgcacagaccccacttcaaccagacctgcatcc tgttcgacggccacgacctgctgtttagcaccgtgaccccctgcctgcaccagggcttctacct gatcgacgagctgagatacgtgaagatcaccctgaccgaggatttcttcgtggtcaccgtgtcc atcgacgacgacacccccatgctgctgatcttcggccacctgcccagagtgctgttcaaggccc cctaccagcgggacaacttcatcctgcggcagaccgagaagcacgagctgctggtgctggtcaa gaaggaccagctgaaccggcactcctacctgaaggaccccgacttcctggacgccgccctggac ttcaactacctggacctgagcgccctgctgagaaacagcttccacagatacgccgtggacgtgc tgaagtccggacggtgccagatgctcgatcggcggaccgtggagatggccttcgcctatgccct cgccctgttcgccgctgccagacaggaagaggctggcgcccaggtgt cagtgcccagagccctg gatagacaggccgccctgctgcagatccaggaattcatgatcacctgcctgagccagacccccc ctagaaccaccctgctgctgtaccccacagccgtggatctggccaagagggccctgtggacccc caaccagatcaccgacatcacaagcctcgtgcggctcgtgtacatcctgagcaagcagaaccag cagcacctgatcccccagtgggccctgagacagatcgccgacttcgccctgaagctgcacaaga cccatctggccagctttctgagcgccttcgccaggcaggaactgtacctgatgggcagcctggt ccacagcatgctggtgcataccaccgagcggcgggagatcttcatcgtggagacaggcctgtgt agcctggccgagctgtcccactttacccagctgctggcccaccctcaccacgagtacctgagcg acctgtacaccccctgcagcagcagcggcagacgggaccacagcctggaacggctgaccagact gttccccgatgccaccgtgcctgctacagtgcctgccgccctgtccatcctgtccaccatgcag cccagcaccctggaaaccttccccgacctgttctgcctgcccctgggcgagagctttagcgccc tgaccgtgtccgagcacgtgtcctacatcgtgaccaatcagtacctgatcaagggcatcagcta ccccgtgtccaccacagtcgtgggccagagcctgatcatcacccagaccgacagccagaccaag tgcgagctgacccggaacatgcacaccacacacagcatcaccgtggccctgaacatcagcctgg aaaactgcgctttctgtcagtctgccctgctggaatacgacgatacccagggcgtgatcaacat catgtacatgcacgacagcgacgacgtgctgttcgccctggacccctacaacgaggtggtggtg tccagcc cccggacccactacctgatgctgctgaagaacggcaccgtgctggaagtgaccgacg tggtggtggacgccaccgacagcagactgctgatgatgagcgtgtacgccctgagcgccatcat cggcatctacctgctgtaccggatgctgaaaacctgctgataatctagacggcgcgcccaccca gcggccgcctataactctctacggctaacctgaatggactacgacatagtctagtcgacgccac catgtgcagaaggcccgactgcggcttcagcttcagccctggacccgtgatcctgctgtggtgc tgcctgctgctgcctatcgtgtcctctgccgccgtgtctgtggcccctacagccgccgagaagg tgccagccgagtgccccgagctgaccagaagatgcctgctgggcgaggtgttcgagggcgacaa gtacgagagctggctgcggcccctggtcaacgtgaccggcagagatggccccctgagccagctg atccggtacagacccgtgacccccgaggccgccaatagcgtgctgctggacgaggccttcctgg ataccctggccctgctgtacaacaaccccgaccagctgagagccctgctgaccctgctgtccag cgacaccgcccccagatggatgaccgtgatgcggggctacagcgagtgtggagatggcagccct gccgtgtacacctgcgtggacgacctgtgcagaggctacgacctgaccagactgagctacggcc ggtccatcttcacagagcacgtgctgggcttcgagctggtgccccccagcctgttcaacgtggt ggtggccatccggaacgaggccaccagaaccaacagagccgtgcggctgcctgtgtctacagcc gctgcacctgagggcatcacactgttctacggcctgtacaacgccgtgaaagagttctgcctcc ggcaccagctggatccccccctgctgagacac ctggacaagtactacgccggcctgcccccaga gctgaagcagaccagagtgaacctgcccgcccacagcagatatggccctcaggccgtggacgcc agatgataatctagacggcgcgcccacccaatcgatgtacttccgaggaactcacgtgcataat gcatcaggctggtacattagatccccgcttaccgcgggcaatatagcaacactaaaaactcgat gtacttccgaggaagcgcagtgcataatgctgcgcagtgttgccacataaccactatattaacc atttatctagcggacgccaaaaactcaatgtatttctgaggaagcgtggtgcataatgccacgc agcgtctgcataacttttattatttcttttattaatcaacaaaattttgtttttaacatttcaa aaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaagggtcggcatggcatctccacctcct cgcggtccgacctgggcatccgaaggaggacgcacgtccactcggatggctaagggagagccac gagctcctgtttaaaccagctccaattcgccctatagtgagtcgtattacgcgcgctcactggc cgtcgttttacaacgtcgtgactgggaaaaccctggcgttacccaacttaatcgccttgcagca catccccctttcgccagctggcgtaatagcgaagaggcccgcaccgatcgcccttcccaacagt tgcgcagcctgaatggcgaatgggacgcgccctgtagcggcgcattaagcgcggcgggtgtggt ggttacgcgcagcgtgaccgctacacttgccagcgccctagcgcccgctcctttcgctttcttc ccttcctttctcgccacgttcgccggctttccccgtcaagctctaaatcgggggctccctttag ggttccgatttagtgctttacggcacctcgaccccaaaaaacttgattagggtgatg gttcacg tagtgggccatcgccctgatagacggtttttcgccctttgacgttggagtccacgttctttaat agtggactcttgttccaaactggaacaacactcaaccctatctcggtctattcttttgatttat aagggattttgccgatttcggcctattggttaaaaaatgagctgatttaacaaaaatttaacgc gaattttaacaaaatattaacgcttacaatttaggtggcacttttcggggaaatgtgcgcggaa cccctatttgtttatttttctaaatacattcaaatatgtatccgctcatgagacaataaccctg ataaatgcttcaataatattgaaaaaggaagagtatgagtattcaacatttccgtgtcgccctt attcccttttttgcggcattttgccttcctgtttttgctcacccagaaacgctggtgaaagtaa aagatgctgaagatcagttgggtgcacgagtgggttacatcgaactggatctcaacagcggtaa gatccttgagagttttcgccccgaagaacgttttccaatgatgagcacttttaaagttctgcta tgtggcgcggtattatcccgtattgacgccgggcaagagcaactcggtcgccgcatacactatt ctcagaatgacttggttgagtactcaccagtcacagaaaagcatcttacggatggcatgacagt aagagaattatgcagtgctgccataaccatgagtgataacactgcggccaacttacttctgaca acgatcggaggaccgaaggagctaaccgcttttttgcacaacatgggggatcatgtaactcgcc ttgatcgttgggaaccggagctgaatgaagccataccaaacgacgagcgtgacaccacgatgcc tgtagcaatggcaacaacgttgcgcaaactattaactggcgaactacttactctagcttcccgg caacaattaatagactg gatggaggcggataaagttgcaggaccacttctgcgctcggcccttc cggctggctggtttattgctgataaatctggagccggtgagcgtgggtctcgcggtatcattgc agcactggggccagatggtaagccctcccgtatcgtagttatctacacgacggggagtcaggca actatggatgaacgaaatagacagatcgctgagataggtgcctcactgattaagcattggtaac tgtcagaccaagtttactcatatatactttagattgatttaaaacttcatttttaatttaaaag gatctaggtgaagatcctttttgataatctcatgaccaaaatcccttaacgtgagttttcgttc cactgagcgtcagaccccgtagaaaagatcaaaggatcttcttgagatcctttttttctgcgcg taatctgctgcttgcaaacaaaaaaaccaccgctaccagcggtggtttgtttgccggatcaaga gctaccaactctttttccgaaggtaactggcttcagcagagcgcagataccaaatactgttctt ctagtgtagccgtagttaggccaccacttcaagaactctgtagcaccgcctacatacctcgctc tgctaatcctgttaccagtggctgctgccagtggcgataagtcgtgtcttaccgggttggactc aagacgatagttaccggataaggcgcagcggtcgggctgaacggggggttcgtgcacacagccc agcttggagcgaacgacctacaccgaactgagatacctacagcgtgagctatgagaaagcgcca cgcttcccgaagggagaaaggcggacaggtatccggtaagcggcagggtcggaacaggagagcg cacgagggagcttccagggggaaacgcctggtatctttatagtcctgtcgggtttcgccacctc tgacttgagcgtcgatttttgtgatgctcgtcaggggggcgg agcctatggaaaaacgccagca acgcggcctttttacggttcctggccttttgctggccttttgctcacatgttctttcctgcgtt atcccctgattctgtggataaccgtattaccgcctttgagtgagctgataccgctcgccgcagc cgaacgaccgagcgcagcgagtcagtgagcgaggaagcggaagagcgcccaatacgcaaaccgc ctctccccgcgcgttggccgattcattaatgcagctggcacgacaggtttcccgactggaaagc gggcagtgagcgcaacgcaattaatgtgagttagctcactcattaggcaccccaggctttacac tttatgctcccggctcgtatgttgtgtggaattgtgagcggataacaatttcacacaggaaaca gctatgaccatgattacgccaagcgcgcaattaaccctcactaaagggaacaaaagctgggtac cggcgcca vector modified PVCR sun-SGP SGP gH gL-gO cgcgtcggctacaattaatacataaccttatgtatcatacacatacgatttaggtgacactata gatgggcggcgcatgagagaagcccagaccaattacctacccaaaatggagaaagttcacgttg acatcgaggaagacagcccattcctcagagctttgcagcggagcttcccgcagtttgaggtaga agccaagcaggtcactgataatgaccatgctaatgccagagcgttttcgcatctggcttcaaaa ctgatcgaaacggaggtggacccatccgacacgatccttgacattggaagtgcgcccgcccgca gaatgtattctaagcacaagtatcattgtatctgtccgatgagatgtgcggaagatccggacag attgtataagtatgcaactaagctgaagaaaaactgtaaggaaataactgataaggaattggac aagaaaatgaag gagctcgccgccgtcatgagcgaccctgacctggaaactgagactatgtgcc tgacggaccgacaagtctctatcaccaagccaataagggagttagagtcgcctactggataggc tttgacaccaccccttttatgtttaagaacttggctggagcatatccatcatactctaccaact gggccgacgaaaccgtgttaacggctcgtaacataggcctatgcagctctgacgttatggagcg tccacgacgacgagtcgtgtcgctacgaagggcaagtcgctgtttaccaggatgtatacgcggt gtcacgtagagggatgtccattcttagaaagaagtatttgaaaccatccaacaatgttctattc tctgttggctcgaccatctaccacgagaagagggacttactgaggagctggcacctgccgtctg tatttcacttacgtggcaagcaaaattacacatgtcggtgtgagactatagttagttgcgacgg gtacgtcgttaaaagaatagctatcagtccaggcctgtatgggaagccttcaggctatgctgct acgatgcaccgcgagggattcttgtgctgcaaagtgacagacacattgaacggggagagggtct cttttcccgtgtgcacgtatgtgccagctacattgtgtgaccaaatgactggcatactggcaac agatgtcagtgcggacgacgcgcaaaaactgctggttgggctcaaccagcgtatagtcgtcaac ggtcgcacccagagaaacaccaataccatgaaaaattaccttttgcccgtagtggcccaggcat ttgctaggtgggcaaaggaatataaggaagatcaagaagatgaaaggccactaggactacgaga tagacagttagtcatggggtgttgttgggcttttagaaggcacaagataacatctatttataag cgcccggatacccaaaccatcatcaaagtgaacagcg atttccactcattcgtgctgcccagga taggcagtaacacattggagatcgggctgagaacaagaatcaggaaaatgttagaggagcacaa ggagccgtcacctctcattaccgccgaggacgtacaagaagctaagtgcgcagccgatgaggct aaggaggtgcgtgaagccgaggagttgcgcgcagctctaccacctttggcagctgatgttgagg agcccactctggaagccgatgtagacttgatgttacaagaggctggggccggctcagtggagac acctcgtggcttgataaaggttaccagctacgctggcgaggacaagatcggctcttacgctgtg ctttctccgcaggctgtactcaagagtgaaaaattatcttgcatccaccctctcgctgaacaag tcatagtgataacacactctggccgaaaagggcgttatgccgtggaaccataccatggtaaagt agtggtgccagagggacatgcaatacccgtccaggactttcaagctctgagtgaaagtgccacc attgtgtacaacgaacgtgagttcgtaaacaggtacctgcaccatattgccacacatggaggag cgctgaacactgatgaagaatattacaaaactgtcaagcccagcgagcacgacggcgaatacct gtacgacatcgacaggaaacagtgcgtcaagaaagaactagtcactgggctagggctcacaggc gagctggtggatcctcccttccatgaattcgcctacgagagtctgagaacacgaccagccgctc cttaccaagtaccaaccataggggtgtatggcgtgccaggatcaggcaagtctggcatcattaa aagcgcagtcaccaaaaaagatctagtggtgagcgccaagaaagaaaactgtgcagaaattata agggacgtcaagaaaatgaaagggctggacgtcaatgccagaactgtggactcagtgctctt ga atggatgcaaacaccccgtagagaccctgtatattgacgaagcttttgcttgtcatgcaggtac tctcagagcgctcatagccattataagacctaaaaaggcagtgctctgcggggatcccaaacag tgcggtttttttaacatgatgtgcctgaaagtgcattttaaccacgagatttgcacacaagtct tccacaaaagcatctctcgccgttgcactaaatctgtgacttcggtcgtctcaaccttgtttta cgacaaaaaaatgagaacgacgaatccgaaagagactaagattgtgattgacactaccggcagt accaaacctaagcaggacgatctcattctcacttgtttcagagggtgggtgaagcagttgcaaa tagattacaaaggcaacgaaataatgacggcagctgcctctcaagggctgacccgtaaaggtgt gtatgccgttcggtacaaggtgaatgaaaatcctctgtacgcacccacctcagaacatgtgaac gtcctactgacccgcacggaggaccgcatcgtgtggaaaacactagccggcgacccatggataa aaacactgactgccaagtaccctgggaatttcactgccacgatagaggagtggcaagcagagca tgatgccatcatgaggcacatcttggagagaccggaccctaccgacgtcttccagaataaggca aacgtgtgttgggccaaggctttagtgccggtgctgaagaccgctggcatagacatgaccactg aacaatggaacactgtggattattttgaaacggacaaagctcactcagcagagatagtattgaa ccaactatgcgtgaggttctttggactcgatctggactccggtctattttctgcacccactgtt ccgttatccattaggaataatcactgggataactccccgtcgcctaacatgtacgggctgaata aagaagtggtccgtcagctctc tcgcaggtacccacaactgcctcgggcagttgccactggaag agtctatgacatgaacactggtacactgcgcaattatgatccgcgcataaacctagtacctgta aacagaagactgcctcatgctttagtcctccaccataatgaacacccacagagtgacttttctt cattcgtcagcaaattgaagggcagaactgtcctggtggtcggggaaaagttgtccgtcccagg caaaatggttgactggttgtcagaccggcctgaggctaccttcagagctcggctggatttaggc atcccaggtgatgtgcccaaatatgacataatatttgttaatgtgaggaccccatataaatacc atcactatcagcagtgtgaagaccatgccattaagcttagcatgttgaccaagaaagcttgtct gcatctgaatcccggcggaacctgtgtcagcataggttatggttacgctgacagggccagcgaa agcatcattggtgctatagcgcggcagttcaagttttcccgggtatgcaaaccgaaatcctcac ttgaagagacggaagttctgtttgtattcattgggtacgatcgcaaggcccgtacgcacaatcc ttacaagctttcatcaaccttgaccaacatttatacaggttccagactccacgaagccggatgt gcaccctcatatcatgtggtgcgaggggatattgccacggccaccgaaggagtgattataaatg ctgctaacagcaaaggacaacctggcggaggggtgtgcggagcgctgtataagaaattcccgga aagcttcgatttacagccgatcgaagtaggaaaagcgcgactggtcaaaggtgcagctaaacat atcattcatgccgtaggaccaaacttcaacaaagtttcggaggttgaaggtgacaaacagttgg cagaggcttatgagtccatcgctaagattgtcaacgataacaattac aagtcagtagcgattcc actgttgtccaccggcatcttttccgggaacaaagatcgactaacccaatcattgaaccatttg ctgacagctttagacaccactgatgcagatgtagccatatactgcagggacaagaaatgggaaa tgactctcaaggaagcagtggctaggagagaagcagtggaggagatatgcatatccgacgactc ttcagtgacagaacctgatgcagagctggtgagggtgcatccgaagagttctttggctggaagg aagggctacagcacaagcgatggcaaaactttctcatatttggaagggaccaagtttcaccagg cggccaaggatatagcagaaattaatgccatgtggcccgttgcaacggaggccaatgagcaggt atgcatgtatatcctcggagaaagcatgagcagtattaggtcgaaatgccccgtcgaagagtcg gaagcctcctcaccacctagcacgctgccttgcttgtgcatccatgccatgactccagaaagag tacagcgcctaaaagcctcacgtccagaacaaattactgtgtgctcatcctttccattgccgaa gtatagaatcactggtgtgcagaagatccaatgctcccagcctatattgttctcaccgaaagtg cctgcgtatattcatccaaggaagtatctcgtggaaacaccaccggtagacgagactccggagc catcggcagagaaccaatccacagaggggacacctgaacaaccaccacttataaccgaggatga gaccaggactagaacgcctgagccgatcatcatcgaagaggaagaagaggatagcataagtttg ctgtcagatggcccgacccaccaggtgctgcaagtcgaggcagacattcacgggccgccctctg tatctagctcatcctggtccattcctcatgcatccgactttgatgtggacagtttatccatact tgacacc ctggagggagctagcgtgaccagcggggcaacgtcagccgagactaactcttacttc gcaaagagtatggagtttctggcgcgaccggtgcctgcgcctcgaacagtattcaggaaccctc cacatcccgctccgcgcacaagaacaccgtcacttgcacccagcagggcctgctcgagagggat cacgggagaaaccgtgggatacgcggttacacacaatagcgagggcttcttgctatgcaaagtt actgacacagtaaaaggagaacgggtatcgttccctgtgtgcacgtacatcccggccaccataa actcgagaaccagcctggtctccaacccgccaggcgtaaatagggtgattacaagagaggagtt tgaggcgttcgtagcacaacaacaatgacggtttgatgcgggtgcatacatcttttcctccgac accggtcaagggcatttacaacaaaaatcagtaaggcaaacggtgctatccgaagtggtgttgg agaggaccgaattggagatttcgtatgccccgcgcctcgaccaagaaaaagaagaattactacg caagaaattacagttaaatcccacacctgctaacagaagcagataccagtccaggaaggtggag aacatgaaagccataacagctagacgtattctgcaaggcctagggcattatttgaaggcagaag gaaaagtggagtgctaccgaaccctgcatcctgttcctttgtattcatctagtgtgaaccgtgc cttttcaagccccaaggtcgcagtggaagcctgtaacgccatgttgaaagagaactttccgact gtggcttcttactgtattattccagagtacgatgcctatttggacatggttgacggagcttcat gctgcttagacactgccagtttttgccctgcaaagctgcgcagctttccaaagaaacactccta tttggaacccacaatacgatcggcagtgcctt cagcgatccagaacacgctccagaacgtcctg gcagctgccacaaaaagaaattgcaatgtcacgcaaatgagagaattgcccgtattggattcgg cggcctttaatgtggaatgcttcaagaaatatgcgtgtaataatgaatattgggaaacgtttaa agaaaaccccatcaggcttactgaagaaaacgtggtaaattacattaccaaattaaaaggacca aaagctgctgctctttttgcgaagacacataatttgaatatgttgcaggacataccaatggaca ggtttgtaatggacttaaagagagacgtgaaagtgactccaggaacaaaacatactgaagaacg gcccaaggtacaggtgatccaggctgccgatccgctagcaacagcgtatctgtgcggaatccac cgagagctggttaggagattaaatgcggtcctgcttccgaacattcatacactgtttgatatgt cggctgaagactttgacgctattatagccgagcacttccagcctggggattgtgttctggaaac tgacatcgcgtcgtttgataaaagtgaggacgacgccatggctctgaccgcgttaatgattctg gaagacttaggtgtggacgcagagctgttgacgctgattgaggcggctttcggcgaaatttcat caatacatttgcccactaaaactaaatttaaattcggagccatgatgaaatctggaatgttcct cacactgtttgtgaacacagtcattaacattgtaatcgcaagcagagtgttgagagaacggcta accggatcaccatgtgcagcattcattggagatgacaatatcgtgaaaggagtcaaatcggaca aattaatggcagacaggtgcgccacctggttgaatatggaagtcaagattatagatgctgtggt gggcgagaaagcgccttatttctgtggagggtttattttgtgtgactccgtgaccgg cacagcg tgccgtgtggcagaccccctaaaaaggctgtttaagcttggcaaacctctggcagcagacgatg aacatgatgatgacaggagaagggcattgcatgaagagtcaacacgctggaaccgagtgggtat tctttcagagctgtgcaaggcagtagaatcaaggtatgaaaccgtaggaacttccatcatagtt atggccatgactactctagctagcagtgttaaatcattcagctacctgagaggggcccctataa ctctctacggctaacctgaatggactacgacatagtctagtcgacgccaccatgaggcctggcc tgccctcctacctgatcatcctggccgtgtgcctgttcagccacctgctgtccagcagatacgg cgccgaggccgtgagcgagcccctggacaaggctttccacctgctgctgaacacctacggcaga cccatccggtttctgcgggagaacaccacccagtgcacctacaacagcagcctgcggaacagca ccgtcgtgagagagaacgccatcagcttcaactttttccagagctacaaccagtactacgtgtt ccacatgcccagatgcctgtttgccggccctctggccgagcagttcctgaaccaggtggacctg accgagacactggaaagataccagcagcggctgaatacctacgccctggtgtccaaggacctgg ccagctaccggtcctttagccagcagctcaaggctcaggatagcctcggcgagcagcctaccac cgtgccccctcccatcgacctgagcatcccccacgtgtggatgcctccccagaccacccctcac ggctggaccgagagccacaccacctccggcctgcacagaccccacttcaaccagacctgcatcc tgttcgacggccacgacctgctgtttagcaccgtgaccccctgcctgcaccagggcttctacct gatcgacgagctgagat acgtgaagatcaccctgaccgaggatttcttcgtggtcaccgtgtcc atcgacgacgacacccccatgctgctgatcttcggccacctgcccagagtgctgttcaaggccc cctaccagcgggacaacttcatcctgcggcagaccgagaagcacgagctgctggtgctggtcaa gaaggaccagctgaaccggcactcctacctgaaggaccccgacttcctggacgccgccctggac ttcaactacctggacctgagcgccctgctgagaaacagcttccacagatacgccgtggacgtgc tgaagtccggacggtgccagatgctcgatcggcggaccgtggagatggccttcgcctatgccct cgccctgttcgccgctgccagacaggaagaggctggcgcccaggtgtcagtgcccagagccctg gatagacaggccgccctgctgcagatccaggaattcatgatcacctgcctgagccagacccccc ctagaaccaccctgctgctgtaccccacagccgtggatctggccaagagggccctgtggacccc caaccagatcaccgacatcacaagcctcgtgcggctcgtgtacatcctgagcaagcagaaccag cagcacctgatcccccagtgggccctgagacagatcgccgacttcgccctgaagctgcacaaga cccatctggccagctttctgagcgccttcgccaggcaggaactgtacctgatgggcagcctggt ccacagcatgctggtgcataccaccgagcggcgggagatcttcatcgtggagacaggcctgtgt agcctggccgagctgtcccactttacccagctgctggcccaccctcaccacgagtacctgagcg acctgtacaccccctgcagcagcagcggcagacgggaccacagcctggaacggctgaccagact gttccccgatgccaccgtgcctgctacagtgcctgccgccct gtccatcctgtccaccatgcag cccagcaccctggaaaccttccccgacctgttctgcctgcccctgggcgagagctttagcgccc tgaccgtgtccgagcacgtgtcctacatcgtgaccaatcagtacctgatcaagggcatcagcta ccccgtgtccaccacagtcgtgggccagagcctgatcatcacccagaccgacagccagaccaag tgcgagctgacccggaacatgcacaccacacacagcatcaccgtggccctgaacatcagcctgg aaaactgcgctttctgtcagtctgccctgctggaatacgacgatacccagggcgtgatcaacat catgtacatgcacgacagcgacgacgtgctgttcgccctggacccctacaacgaggtggtggtg tccagcccccggacccactacctgatgctgctgaagaacggcaccgtgctggaagtgaccgacg tggtggtggacgccaccgactgataatctagacggcgcgcccacccagcggccgcctataactc tctacggctaacctgaatggactacgacatagtctagtcgacgccaccatgtgcagaaggcccg actgcggcttcagcttcagccctggacccgtgatcctgctgtggtgctgcctgctgctgcctat cgtgtcctctgccgccgtgtctgtggcccctacagccgccgagaaggtgccagccgagtgcccc gagctgaccagaagatgcctgctgggcgaggtgttcgagggcgacaagtacgagagctggctgc ggcccctggtcaacgtgaccggcagagatggccccctgagccagctgatccggtacagacccgt gacccccgaggccgccaatagcgtgctgctggacgaggccttcctggataccctggccctgctg tacaacaaccccgaccagctgagagccctgctgaccctgctgtccagcgacaccgcccccagat gg atgaccgtgatgcggggctacagcgagtgtggagatggcagccctgccgtgtacacctgcgt ggacgacctgtgcagaggctacgacctgaccagactgagctacggccggtccatcttcacagag cacgtgctgggcttcgagctggtgccccccagcctgttcaacgtggtggtggccatccggaacg aggccaccagaaccaacagagccgtgcggctgcctgtgtctacagccgctgcacctgagggcat cacactgttctacggcctgtacaacgccgtgaaagagttctgcctccggcaccagctggatccc cccctgctgagacacctggacaagtactacgccggcctgcccccagagctgaagcagaccagag tgaacctgcccgcccacagcagatatggccctcaggccgtggacgccagatgataatctagacg gcgcgcccacccaatcgatctataactctctacggctaacctgaatggactacgacatagtcta gtcgacgccaccatgggcaagaaagaaatgatcatggtcaagggcatccccaagatcatgctgc tgattagcatcacctttctgctgctgtccctgatcaactgcaacgtgctggtcaacagccgggg caccagaagatcctggccctacaccgtgctgtcctaccggggcaaagagatcctgaagaagcag aaagaggacatcctgaagcggctgatgagcaccagcagcgacggctaccggttcctgatgtacc ccagccagcagaaattccacgccatcgtgatcagcatggacaagttcccccaggactacatcct ggccggacccatccggaacgacagcatcacccacatgtggttcgacttctacagcacccagctg cggaagcccgccaaatacgtgtacagcgagtacaaccacaccgcccacaagatcaccctgaggc ctcccccttgtggcaccgtgcccagca tgaactgcctgagcgagatgctgaacgtgtccaagcg gaacgacaccggcgagaagggctgcggcaacttcaccaccttcaaccccatgttcttcaacgtg ccccggtggaacaccaagctgtacatcggcagcaacaaagtgaacgtggacagccagaccatct actttctgggcctgaccgccctgctgctgagatacgcccagcggaactgcacccggtccttcta cctggtcaacgccatgagccggaacctgttccgggtgcccaagtacatcaacggcaccaagctg aagaacaccatgcggaagctgaagcggaagcaggccctggtcaaagagcagccccagaagaaga acaagaagtcccagagcaccaccaccccctacctgagctacaccacctccaccgccttcaacgt gaccaccaacgtgacctacagcgccacagccgccgtgaccagagtggccacaagcaccaccggc taccggcccgacagcaactttatgaagtccatcatggccacccagctgagagatctggccacct gggtgtacaccaccctgcggtacagaaacgagcccttctgcaagcccgaccggaacagaaccgc cgtgagcgagttcatgaagaatacccacgtgctgatcagaaacgagacaccctacaccatctac ggcaccctggacatgagcagcctgtactacaacgagacaatgagcgtggagaacgagacagcca gcgacaacaacgaaaccacccccacctcccccagcacccggttccagcggaccttcatcgaccc cctgtgggactacctggacagcctgctgttcctggacaagatccggaacttcagcctgcagctg cccgcctacggcaatctgaccccccctgagcacagaagggccgccaacctgagcaccctgaaca gcctgtggtggtggagccagtgataatctagacggcgcgcccacccaccgcg ggcaatatagca acactaaaaactcgatgtacttccgaggaagcgcagtgcataatgctgcgcagtgttgccacat aaccactatattaaccatttatctagcggacgccaaaaactcaatgtatttctgaggaagcgtg gtgcataatgccacgcagcgtctgcataacttttattatttcttttattaatcaacaaaatttt gtttttaacatttcaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaagggtcggcat ggcatctccacctcctcgcggtccgacctgggcatccgaaggaggacgcacgtccactcggatg gctaagggagagccacgagctcctgtttaaaccagctccaattcgccctatagtgagtcgtatt acgcgcgctcactggccgtcgttttacaacgtcgtgactgggaaaaccctggcgttacccaact taatcgccttgcagcacatccccctttcgccagctggcgtaatagcgaagaggcccgcaccgat cgcccttcccaacagttgcgcagcctgaatggcgaatgggacgcgccctgtagcggcgcattaa gcgcggcgggtgtggtggttacgcgcagcgtgaccgctacacttgccagcgccctagcgcccgc tcctttcgctttcttcccttcctttctcgccacgttcgccggctttccccgtcaagctctaaat cgggggctccctttagggttccgatttagtgctttacggcacctcgaccccaaaaaacttgatt agggtgatggttcacgtagtgggccatcgccctgatagacggtttttcgccctttgacgttgga gtccacgttctttaatagtggactcttgttccaaactggaacaacactcaaccctatctcggtc tattcttttgatttataagggattttgccgatttcggcctattggttaaaaaatgagctgattt aacaaaaattta acgcgaattttaacaaaatattaacgcttacaatttaggtggcacttttcgg ggaaatgtgcgcggaacccctatttgtttatttttctaaatacattcaaatatgtatccgctca tgagacaataaccctgataaatgcttcaataatattgaaaaaggaagagtatgagtattcaaca tttccgtgtcgcccttattcccttttttgcggcattttgccttcctgtttttgctcacccagaa acgctggtgaaagtaaaagatgctgaagatcagttgggtgcacgagtgggttacatcgaactgg atctcaacagcggtaagatccttgagagttttcgccccgaagaacgttttccaatgatgagcac ttttaaagttctgctatgtggcgcggtattatcccgtattgacgccgggcaagagcaactcggt cgccgcatacactattctcagaatgacttggttgagtactcaccagtcacagaaaagcatctta cggatggcatgacagtaagagaattatgcagtgctgccataaccatgagtgataacactgcggc caacttacttctgacaacgatcggaggaccgaaggagctaaccgcttttttgcacaacatgggg gatcatgtaactcgccttgatcgttgggaaccggagctgaatgaagccataccaaacgacgagc gtgacaccacgatgcctgtagcaatggcaacaacgttgcgcaaactattaactggcgaactact tactctagcttcccggcaacaattaatagactggatggaggcggataaagttgcaggaccactt ctgcgctcggcccttccggctggctggtttattgctgataaatctggagccggtgagcgtgggt ctcgcggtatcattgcagcactggggccagatggtaagccctcccgtatcgtagttatctacac gacggggagtcaggcaactatggatgaacgaaataga cagatcgctgagataggtgcctcactg attaagcattggtaactgtcagaccaagtttactcatatatactttagattgatttaaaacttc atttttaatttaaaaggatctaggtgaagatcctttttgataatctcatgaccaaaatccctta acgtgagttttcgttccactgagcgtcagaccccgtagaaaagatcaaaggatcttcttgagat cctttttttctgcgcgtaatctgctgcttgcaaacaaaaaaaccaccgctaccagcggtggttt gtttgccggatcaagagctaccaactctttttccgaaggtaactggcttcagcagagcgcagat accaaatactgttcttctagtgtagccgtagttaggccaccacttcaagaactctgtagcaccg cctacatacctcgctctgctaatcctgttaccagtggctgctgccagtggcgataagtcgtgtc ttaccgggttggactcaagacgatagttaccggataaggcgcagcggtcgggctgaacgggggg ttcgtgcacacagcccagcttggagcgaacgacctacaccgaactgagatacctacagcgtgag ctatgagaaagcgccacgcttcccgaagggagaaaggcggacaggtatccggtaagcggcaggg tcggaacaggagagcgcacgagggagcttccagggggaaacgcctggtatctttatagtcctgt cgggtttcgccacctctgacttgagcgtcgatttttgtgatgctcgtcaggggggcggagccta tggaaaaacgccagcaacgcggcctttttacggttcctggccttttgctggccttttgctcaca tgttctttcctgcgttatcccctgattctgtggataaccgtattaccgcctttgagtgagctga taccgctcgccgcagccgaacgaccgagcgcagcgagtcagtgagcgaggaagcggaagagc gc ccaatacgcaaaccgcctctccccgcgcgttggccgattcattaatgcagctggcacgacaggt ttcccgactggaaagcgggcagtgagcgcaacgcaattaatgtgagttagctcactcattaggc accccaggctttacactttatgctcccggctcgtatgttgtgtggaattgtgagcggataacaa tttcacacaggaaacagctatgaccatgattacgccaagcgcgcaattaaccctcactaaagggaacaaaagctgggtaccggcgcca vector modified PVCR gH FL-SGP gL-gO SGP cgcgtcggctacaattaatacataaccttatgtatcatacacatacgatttaggtgacactata gatgggcggcgcatgagagaagcccagaccaattacctacccaaaatggagaaagttcacgttg acatcgaggaagacagcccattcctcagagctttgcagcggagcttcccgcagtttgaggtaga agccaagcaggtcactgataatgaccatgctaatgccagagcgttttcgcatctggcttcaaaa ctgatcgaaacggaggtggacccatccgacacgatccttgacattggaagtgcgcccgcccgca gaatgtattctaagcacaagtatcattgtatctgtccgatgagatgtgcggaagatccggacag attgtataagtatgcaactaagctgaagaaaaactgtaaggaaataactgataaggaattggac aagaaaatgaaggagctcgccgccgtcatgagcgaccctgacctggaaactgagactatgtgcc tccacgacgacgagtcgtgtcgctacgaagggcaagtcgctgtttaccaggatgtatacgcggt tgacggaccgacaagtctctatcaccaagccaataagggagttagagtcgcctactggataggc tttgacaccacccctttt atgtttaagaacttggctggagcatatccatcatactctaccaact gggccgacgaaaccgtgttaacggctcgtaacataggcctatgcagctctgacgttatggagcg gtcacgtagagggatgtccattcttagaaagaagtatttgaaaccatccaacaatgttctattc tctgttggctcgaccatctaccacgagaagagggacttactgaggagctggcacctgccgtctg tatttcacttacgtggcaagcaaaattacacatgtcggtgtgagactatagttagttgcgacgg gtacgtcgttaaaagaatagctatcagtccaggcctgtatgggaagccttcaggctatgctgct acgatgcaccgcgagggattcttgtgctgcaaagtgacagacacattgaacggggagagggtct cttttcccgtgtgcacgtatgtgccagctacattgtgtgaccaaatgactggcatactggcaac agatgtcagtgcggacgacgcgcaaaaactgctggttgggctcaaccagcgtatagtcgtcaac ggtcgcacccagagaaacaccaataccatgaaaaattaccttttgcccgtagtggcccaggcat ttgctaggtgggcaaaggaatataaggaagatcaagaagatgaaaggccactaggactacgaga tagacagttagtcatggggtgttgttgggcttttagaaggcacaagataacatctatttataag cgcccggatacccaaaccatcatcaaagtgaacagcgatttccactcattcgtgctgcccagga taggcagtaacacattggagatcgggctgagaacaagaatcaggaaaatgttagaggagcacaa ggagccgtcacctctcattaccgccgaggacgtacaagaagctaagtgcgcagccgatgaggct aaggaggtgcgtgaagccgaggagttgcgcgcagctctaccac ctttggcagctgatgttgagg agcccactctggaagccgatgtagacttgatgttacaagaggctggggccggctcagtggagac acctcgtggcttgataaaggttaccagctacgctggcgaggacaagatcggctcttacgctgtg ctttctccgcaggctgtactcaagagtgaaaaattatcttgcatccaccctctcgctgaacaag tcatagtgataacacactctggccgaaaagggcgttatgccgtggaaccataccatggtaaagt agtggtgccagagggacatgcaatacccgtccaggactttcaagctctgagtgaaagtgccacc attgtgtacaacgaacgtgagttcgtaaacaggtacctgcaccatattgccacacatggaggag cgctgaacactgatgaagaatattacaaaactgtcaagcccagcgagcacgacggcgaatacct gtacgacatcgacaggaaacagtgcgtcaagaaagaactagtcactgggctagggctcacaggc gagctggtggatcctcccttccatgaattcgcctacgagagtctgagaacacgaccagccgctc cttaccaagtaccaaccataggggtgtatggcgtgccaggatcaggcaagtctggcatcattaa aagcgcagtcaccaaaaaagatctagtggtgagcgccaagaaagaaaactgtgcagaaattata agggacgtcaagaaaatgaaagggctggacgtcaatgccagaactgtggactcagtgctcttga atggatgcaaacaccccgtagagaccctgtatattgacgaagcttttgcttgtcatgcaggtac tctcagagcgctcatagccattataagacctaaaaaggcagtgctctgcggggatcccaaacag tgcggtttttttaacatgatgtgcctgaaagtgcattttaaccacgagatttgcacacaagtct tcc acaaaagcatctctcgccgttgcactaaatctgtgacttcggtcgtctcaaccttgtttta cgacaaaaaaatgagaacgacgaatccgaaagagactaagattgtgattgacactaccggcagt accaaacctaagcaggacgatctcattctcacttgtttcagagggtgggtgaagcagttgcaaa tagattacaaaggcaacgaaataatgacggcagctgcctctcaagggctgacccgtaaaggtgt gtatgccgttcggtacaaggtgaatgaaaatcctctgtacgcacccacctcagaacatgtgaac gtcctactgacccgcacggaggaccgcatcgtgtggaaaacactagccggcgacccatggataa aaacactgactgccaagtaccctgggaatttcactgccacgatagaggagtggcaagcagagca tgatgccatcatgaggcacatcttggagagaccggaccctaccgacgtcttccagaataaggca aacgtgtgttgggccaaggctttagtgccggtgctgaagaccgctggcatagacatgaccactg aacaatggaacactgtggattattttgaaacggacaaagctcactcagcagagatagtattgaa ccaactatgcgtgaggttctttggactcgatctggactccggtctattttctgcacccactgtt ccgttatccattaggaataatcactgggataactccccgtcgcctaacatgtacgggctgaata aagaagtggtccgtcagctctctcgcaggtacccacaactgcctcgggcagttgccactggaag agtctatgacatgaacactggtacactgcgcaattatgatccgcgcataaacctagtacctgta aacagaagactgcctcatgctttagtcctccaccataatgaacacccacagagtgacttttctt cattcgtcagcaaattgaagggcagaac tgtcctggtggtcggggaaaagttgtccgtcccagg caaaatggttgactggttgtcagaccggcctgaggctaccttcagagctcggctggatttaggc atcccaggtgatgtgcccaaatatgacataatatttgttaatgtgaggaccccatataaatacc atcactatcagcagtgtgaagaccatgccattaagcttagcatgttgaccaagaaagcttgtct gcatctgaatcccggcggaacctgtgtcagcataggttatggttacgctgacagggccagcgaa agcatcattggtgctatagcgcggcagttcaagttttcccgggtatgcaaaccgaaatcctcac ttgaagagacggaagttctgtttgtattcattgggtacgatcgcaaggcccgtacgcacaatcc ttacaagctttcatcaaccttgaccaacatttatacaggttccagactccacgaagccggatgt gcaccctcatatcatgtggtgcgaggggatattgccacggccaccgaaggagtgattataaatg ctgctaacagcaaaggacaacctggcggaggggtgtgcggagcgctgtataagaaattcccgga aagcttcgatttacagccgatcgaagtaggaaaagcgcgactggtcaaaggtgcagctaaacat atcattcatgccgtaggaccaaacttcaacaaagtttcggaggttgaaggtgacaaacagttgg cagaggcttatgagtccatcgctaagattgtcaacgataacaattacaagtcagtagcgattcc actgttgtccaccggcatcttttccgggaacaaagatcgactaacccaatcattgaaccatttg ctgacagctttagacaccactgatgcagatgtagccatatactgcagggacaagaaatgggaaa tgactctcaaggaagcagtggctaggagagaagcagtggaggagatatgcata tccgacgactc ttcagtgacagaacctgatgcagagctggtgagggtgcatccgaagagttctttggctggaagg aagggctacagcacaagcgatggcaaaactttctcatatttggaagggaccaagtttcaccagg cggccaaggatatagcagaaattaatgccatgtggcccgttgcaacggaggccaatgagcaggt atgcatgtatatcctcggagaaagcatgagcagtattaggtcgaaatgccccgtcgaagagtcg gaagcctcctcaccacctagcacgctgccttgcttgtgcatccatgccatgactccagaaagag tacagcgcctaaaagcctcacgtccagaacaaattactgtgtgctcatcctttccattgccgaa gtatagaatcactggtgtgcagaagatccaatgctcccagcctatattgttctcaccgaaagtg cctgcgtatattcatccaaggaagtatctcgtggaaacaccaccggtagacgagactccggagc catcggcagagaaccaatccacagaggggacacctgaacaaccaccacttataaccgaggatga gaccaggactagaacgcctgagccgatcatcatcgaagaggaagaagaggatagcataagtttg ctgtcagatggcccgacccaccaggtgctgcaagtcgaggcagacattcacgggccgccctctg tatctagctcatcctggtccattcctcatgcatccgactttgatgtggacagtttatccatact tgacaccctggagggagctagcgtgaccagcggggcaacgtcagccgagactaactcttacttc gcaaagagtatggagtttctggcgcgaccggtgcctgcgcctcgaacagtattcaggaaccctc cacatcccgctccgcgcacaagaacaccgtcacttgcacccagcagggcctgctcgagagggat cacgggagaaacc gtgggatacgcggttacacacaatagcgagggcttcttgctatgcaaagtt actgacacagtaaaaggagaacgggtatcgttccctgtgtgcacgtacatcccggccaccataa actcgagaaccagcctggtctccaacccgccaggcgtaaatagggtgattacaagagaggagtt tgaggcgttcgtagcacaacaacaatgacggtttgatgcgggtgcatacatcttttcctccgac accggtcaagggcatttacaacaaaaatcagtaaggcaaacggtgctatccgaagtggtgttgg agaggaccgaattggagatttcgtatgccccgcgcctcgaccaagaaaaagaagaattactacg caagaaattacagttaaatcccacacctgctaacagaagcagataccagtccaggaaggtggag aacatgaaagccataacagctagacgtattctgcaaggcctagggcattatttgaaggcagaag gaaaagtggagtgctaccgaaccctgcatcctgttcctttgtattcatctagtgtgaaccgtgc cttttcaagccccaaggtcgcagtggaagcctgtaacgccatgttgaaagagaactttccgact gtggcttcttactgtattattccagagtacgatgcctatttggacatggttgacggagcttcat gctgcttagacactgccagtttttgccctgcaaagctgcgcagctttccaaagaaacactccta tttggaacccacaatacgatcggcagtgccttcagcgatccagaacacgctccagaacgtcctg gcagctgccacaaaaagaaattgcaatgtcacgcaaatgagagaattgcccgtattggattcgg cggcctttaatgtggaatgcttcaagaaatatgcgtgtaataatgaatattgggaaacgtttaa agaaaaccccatcaggcttactgaagaaaacgtggtaa attacattaccaaattaaaaggacca aaagctgctgctctttttgcgaagacacataatttgaatatgttgcaggacataccaatggaca ggtttgtaatggacttaaagagagacgtgaaagtgactccaggaacaaaacatactgaagaacg gcccaaggtacaggtgatccaggctgccgatccgctagcaacagcgtatctgtgcggaatccac cgagagctggttaggagattaaatgcggtcctgcttccgaacattcatacactgtttgatatgt cggctgaagactttgacgctattatagccgagcacttccagcctggggattgtgttctggaaac tgacatcgcgtcgtttgataaaagtgaggacgacgccatggctctgaccgcgttaatgattctg gaagacttaggtgtggacgcagagctgttgacgctgattgaggcggctttcggcgaaatttcat caatacatttgcccactaaaactaaatttaaattcggagccatgatgaaatctggaatgttcct cacactgtttgtgaacacagtcattaacattgtaatcgcaagcagagtgttgagagaacggcta accggatcaccatgtgcagcattcattggagatgacaatatcgtgaaaggagtcaaatcggaca aattaatggcagacaggtgcgccacctggttgaatatggaagtcaagattatagatgctgtggt gggcgagaaagcgccttatttctgtggagggtttattttgtgtgactccgtgaccggcacagcg tgccgtgtggcagaccccctaaaaaggctgtttaagcttggcaaacctctggcagcagacgatg aacatgatgatgacaggagaagggcattgcatgaagagtcaacacgctggaaccgagtgggtat tctttcagagctgtgcaaggcagtagaatcaaggtatgaaaccgtaggaacttccatcatagt t atggccatgactactctagctagcagtgttaaatcattcagctacctgagaggggcccctataa ctctctacggctaacctgaatggactacgacatagtctagtcgacgccaccatgaggcctggcc tgccctcctacctgatcatcctggccgtgtgcctgttcagccacctgctgtccagcagatacgg cgccgaggccgtgagcgagcccctggacaaggctttccacctgctgctgaacacctacggcaga cccatccggtttctgcgggagaacaccacccagtgcacctacaacagcagcctgcggaacagca ccgtcgtgagagagaacgccatcagcttcaactttttccagagctacaaccagtactacgtgtt ccacatgcccagatgcctgtttgccggccctctggccgagcagttcctgaaccaggtggacctg accgagacactggaaagataccagcagcggctgaatacctacgccctggtgtccaaggacctgg ccagctaccggtcctttagccagcagctcaaggctcaggatagcctcggcgagcagcctaccac cgtgccccctcccatcgacctgagcatcccccacgtgtggatgcctccccagaccacccctcac ggctggaccgagagccacaccacctccggcctgcacagaccccacttcaaccagacctgcatcc tgttcgacggccacgacctgctgtttagcaccgtgaccccctgcctgcaccagggcttctacct gatcgacgagctgagatacgtgaagatcaccctgaccgaggatttcttcgtggtcaccgtgtcc atcgacgacgacacccccatgctgctgatcttcggccacctgcccagagtgctgttcaaggccc cctaccagcgggacaacttcatcctgcggcagaccgagaagcacgagctgctggtgctggtcaa gaaggaccagctgaaccggcact cctacctgaaggaccccgacttcctggacgccgccctggac ttcaactacctggacctgagcgccctgctgagaaacagcttccacagatacgccgtggacgtgc tgaagtccggacggtgccagatgctcgatcggcggaccgtggagatggccttcgcctatgccct cgccctgttcgccgctgccagacaggaagaggctggcgcccaggtgtcagtgcccagagccctg gatagacaggccgccctgctgcagatccaggaattcatgatcacctgcctgagccagacccccc ctagaaccaccctgctgctgtaccccacagccgtggatctggccaagagggccctgtggacccc caaccagatcaccgacatcacaagcctcgtgcggctcgtgtacatcctgagcaagcagaaccag cagcacctgatcccccagtgggccctgagacagatcgccgacttcgccctgaagctgcacaaga cccatctggccagctttctgagcgccttcgccaggcaggaactgtacctgatgggcagcctggt ccacagcatgctggtgcataccaccgagcggcgggagatcttcatcgtggagacaggcctgtgt agcctggccgagctgtcccactttacccagctgctggcccaccctcaccacgagtacctgagcg acctgtacaccccctgcagcagcagcggcagacgggaccacagcctggaacggctgaccagact gttccccgatgccaccgtgcctgctacagtgcctgccgccctgtccatcctgtccaccatgcag cccagcaccctggaaaccttccccgacctgttctgcctgcccctgggcgagagctttagcgccc tgaccgtgtccgagcacgtgtcctacatcgtgaccaatcagtacctgatcaagggcatcagcta ccccgtgtccaccacagtcgtgggccagagcctgatcatcacccagac cgacagccagaccaag tgcgagctgacccggaacatgcacaccacacacagcatcaccgtggccctgaacatcagcctgg aaaactgcgctttctgtcagtctgccctgctggaatacgacgatacccagggcgtgatcaacat catgtacatgcacgacagcgacgacgtgctgttcgccctggacccctacaacgaggtggtggtg tccagcccccggacccactacctgatgctgctgaagaacggcaccgtgctggaagtgaccgacg tggtggtggacgccaccgacagcagactgctgatgatgagcgtgtacgccctgagcgccatcat cggcatctacctgctgtaccggatgctgaaaacctgctgataatctagacggcgcgcccaccca gcggccgcctataactctctacggctaacctgaatggactacgacatagtctagtcgacgccac catgtgcagaaggcccgactgcggcttcagcttcagccctggacccgtgatcctgctgtggtgc tgcctgctgctgcctatcgtgtcctctgccgccgtgtctgtggcccctacagccgccgagaagg tgccagccgagtgccccgagctgaccagaagatgcctgctgggcgaggtgttcgagggcgacaa gtacgagagctggctgcggcccctggtcaacgtgaccggcagagatggccccctgagccagctg atccggtacagacccgtgacccccgaggccgccaatagcgtgctgctggacgaggccttcctgg ataccctggccctgctgtacaacaaccccgaccagctgagagccctgctgaccctgctgtccag cgacaccgcccccagatggatgaccgtgatgcggggctacagcgagtgtggagatggcagccct gccgtgtacacctgcgtggacgacctgtgcagaggctacgacctgaccagactgagctacggcc ggtccatc ttcacagagcacgtgctgggcttcgagctggtgccccccagcctgttcaacgtggt ggtggccatccggaacgaggccaccagaaccaacagagccgtgcggctgcctgtgtctacagcc gctgcacctgagggcatcacactgttctacggcctgtacaacgccgtgaaagagttctgcctcc ggcaccagctggatccccccctgctgagacacctggacaagtactacgccggcctgcccccaga gctgaagcagaccagagtgaacctgcccgcccacagcagatatggccctcaggccgtggacgcc agatgataatctagacggcgcgcccacccaatcgatctataactctctacggctaacctgaatg gactacgacatagtctagtcgacgccaccatgggcaagaaagaaatgatcatggtcaagggcat ccccaagatcatgctgctgattagcatcacctttctgctgctgtccctgatcaactgcaacgtg ctggtcaacagccggggcaccagaagatcctggccctacaccgtgctgtcctaccggggcaaag agatcctgaagaagcagaaagaggacatcctgaagcggctgatgagcaccagcagcgacggcta ccggttcctgatgtaccccagccagcagaaattccacgccatcgtgatcagcatggacaagttc ccccaggactacatcctggccggacccatccggaacgacagcatcacccacatgtggttcgact tctacagcacccagctgcggaagcccgccaaatacgtgtacagcgagtacaaccacaccgccca caagatcaccctgaggcctcccccttgtggcaccgtgcccagcatgaactgcctgagcgagatg ctgaacgtgtccaagcggaacgacaccggcgagaagggctgcggcaacttcaccaccttcaacc ccatgttcttcaacgtgccccggtggaacacca agctgtacatcggcagcaacaaagtgaacgt ggacagccagaccatctactttctgggcctgaccgccctgctgctgagatacgcccagcggaac tgcacccggtccttctacctggtcaacgccatgagccggaacctgttccgggtgcccaagtaca tcaacggcaccaagctgaagaacaccatgcggaagctgaagcggaagcaggccctggtcaaaga gcagccccagaagaagaacaagaagtcccagagcaccaccaccccctacctgagctacaccacc tccaccgccttcaacgtgaccaccaacgtgacctacagcgccacagccgccgtgaccagagtgg ccacaagcaccaccggctaccggcccgacagcaactttatgaagtccatcatggccacccagct gagagatctggccacctgggtgtacaccaccctgcggtacagaaacgagcccttctgcaagccc gaccggaacagaaccgccgtgagcgagttcatgaagaatacccacgtgctgatcagaaacgaga caccctacaccatctacggcaccctggacatgagcagcctgtactacaacgagacaatgagcgt ggagaacgagacagccagcgacaacaacgaaaccacccccacctcccccagcacccggttccag cggaccttcatcgaccccctgtgggactacctggacagcctgctgttcctggacaagatccgga acttcagcctgcagctgcccgcctacggcaatctgaccccccctgagcacagaagggccgccaa cctgagcaccctgaacagcctgtggtggtggagccagtgataatctagacggcgcgcccaccca ccgcgggcaatatagcaacactaaaaactcgatgtacttccgaggaagcgcagtgcataatgct gcgcagtgttgccacataaccactatattaaccatttatctagcggacgccaaaaact caatgt atttctgaggaagcgtggtgcataatgccacgcagcgtctgcataacttttattatttctttta ttaatcaacaaaattttgtttttaacatttcaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa aaaaaaagggtcggcatggcatctccacctcctcgcggtccgacctgggcatccgaaggaggac gcacgtccactcggatggctaagggagagccacgagctcctgtttaaaccagctccaattcgcc ctatagtgagtcgtattacgcgcgctcactggccgtcgttttacaacgtcgtgactgggaaaac cctggcgttacccaacttaatcgccttgcagcacatccccctttcgccagctggcgtaatagcg aagaggcccgcaccgatcgcccttcccaacagttgcgcagcctgaatggcgaatgggacgcgcc ctgtagcggcgcattaagcgcggcgggtgtggtggttacgcgcagcgtgaccgctacacttgcc agcgccctagcgcccgctcctttcgctttcttcccttcctttctcgccacgttcgccggctttc cccgtcaagctctaaatcgggggctccctttagggttccgatttagtgctttacggcacctcga ccccaaaaaacttgattagggtgatggttcacgtagtgggccatcgccctgatagacggttttt cgccctttgacgttggagtccacgttctttaatagtggactcttgttccaaactggaacaacac tcaaccctatctcggtctattcttttgatttataagggattttgccgatttcggcctattggtt aaaaaatgagctgatttaacaaaaatttaacgcgaattttaacaaaatattaacgcttacaatt taggtggcacttttcggggaaatgtgcgcggaacccctatttgtttatttttctaaatacattc aaatatgtatccgctcat gagacaataaccctgataaatgcttcaataatattgaaaaaggaag agtatgagtattcaacatttccgtgtcgcccttattcccttttttgcggcattttgccttcctg tttttgctcacccagaaacgctggtgaaagtaaaagatgctgaagatcagttgggtgcacgagt gggttacatcgaactggatctcaacagcggtaagatccttgagagttttcgccccgaagaacgt tttccaatgatgagcacttttaaagttctgctatgtggcgcggtattatcccgtattgacgccg ggcaagagcaactcggtcgccgcatacactattctcagaatgacttggttgagtactcaccagt cacagaaaagcatcttacggatggcatgacagtaagagaattatgcagtgctgccataaccatg agtgataacactgcggccaacttacttctgacaacgatcggaggaccgaaggagctaaccgctt ttttgcacaacatgggggatcatgtaactcgccttgatcgttgggaaccggagctgaatgaagc cataccaaacgacgagcgtgacaccacgatgcctgtagcaatggcaacaacgttgcgcaaacta ttaactggcgaactacttactctagcttcccggcaacaattaatagactggatggaggcggata aagttgcaggaccacttctgcgctcggcccttccggctggctggtttattgctgataaatctgg agccggtgagcgtgggtctcgcggtatcattgcagcactggggccagatggtaagccctcccgt atcgtagttatctacacgacggggagtcaggcaactatggatgaacgaaatagacagatcgctg agataggtgcctcactgattaagcattggtaactgtcagaccaagtttactcatatatacttta gattgatttaaaacttcatttttaatttaaaaggatctaggtg aagatcctttttgataatctc atgaccaaaatcccttaacgtgagttttcgttccactgagcgtcagaccccgtagaaaagatca aaggatcttcttgagatcctttttttctgcgcgtaatctgctgcttgcaaacaaaaaaaccacc gctaccagcggtggtttgtttgccggatcaagagctaccaactctttttccgaaggtaactggc ttcagcagagcgcagataccaaatactgttcttctagtgtagccgtagttaggccaccacttca agaactctgtagcaccgcctacatacctcgctctgctaatcctgttaccagtggctgctgccag tggcgataagtcgtgtcttaccgggttggactcaagacgatagttaccggataaggcgcagcgg tcgggctgaacggggggttcgtgcacacagcccagcttggagcgaacgacctacaccgaactga gatacctacagcgtgagctatgagaaagcgccacgcttcccgaagggagaaaggcggacaggta tccggtaagcggcagggtcggaacaggagagcgcacgagggagcttccagggggaaacgcctgg tatctttatagtcctgtcgggtttcgccacctctgacttgagcgtcgatttttgtgatgctcgt caggggggcggagcctatggaaaaacgccagcaacgcggcctttttacggttcctggccttttg ctggccttttgctcacatgttctttcctgcgttatcccctgattctgtggataaccgtattacc gcctttgagtgagctgataccgctcgccgcagccgaacgaccgagcgcagcgagtcagtgagcg aggaagcggaagagcgcccaatacgcaaaccgcctctccccgcgcgttggccgattcattaatg tag cagctggcacgacaggtttcccgactggaaagcgggcagtgagcgcaacgcaattaatgtgagt ctcactcattaggcaccccaggctttacactttatgctcccggctcgtatgttgtgtggaa ttgtgagcggataacaatttcacacaggaaacagctatgaccatgattacgccaagcgcgcaat taaccctcactaaagggacaaaagctg5g SGP-gH-gL-SGP-SGP-UL128-2A-UL130-2Amod-UL131 ATAGGCGGCGCATGAGAGAAGCCCAGACCAATTACCTACCCAAAATGGAGAAAGTTCACGTTGACATCGA GGAAGACAGCCCATTCCTCAGAGCTTTGCAGCGGAGCTTCCCGCAGTTTGAGGTAGAAGCCAAGCAGGTC ACTGATAATGACCATGCTAATGCCAGAGCGTTTTCGCATCTGGCTTCAAAACTGATCGAAACGGAGGTGG ACCCATCCGACACGATCCTTGACATTGGAAGTGCGCCCGCCCGCAGAATGTATTCTAAGCACAAGTATCA TTGTATCTGTCCGATGAGATGTGCGGAAGATCCGGACAGATTGTATAAGTATGCAACTAAGCTGAAGAAA AACTGTAAGGAAATAACTGATAAGGAATTGGACAAGAAAATGAAGGAGCTCGCCGCCGTCATGAGCGACC CTGACCTGGAAACTGAGACTATGTGCCTCCACGACGACGAGTCGTGTCGCTACGAAGGGCAAGTCGCTGT TTACCAGGATGTATACGCGGTTGACGGACCGACAAGTCTCTATCACCAAGCCAATAAGGGAGTTAGAGTC GCCTACTGGATAGGCTTTGACACCACCCCTTTTATGTTTAAGAACTTGGCTGGAGCATATCCATCATACT CTACCAACTGGGCCGACGAAACCGTGTTAACGGCTCGTAACATAGGCCTATGCAGCTCTGACGTTATGGA GCGGTCACGTAGAGGGATGTCCATTCTTAGAAAGAAGTATTTGAAACCATCCAACAATGTTCTATTCTCT GTTGGCTCGACCATCTACCACGAGAAGAGGGACTTACTGAGGAGCTGGCACCTGCCGTCTGTATTTCACT TACGTGGCAAGCAAAATTACACATGTCGGTGTGAGACTATAGTTAGTTGCGACGGGTACGTCGTTAAAAG AATAGCTATCAGTCCAGGCCTGTATGGGAAGC CTTCAGGCTATGCTGCTACGATGCACCGCGAGGGATTC TTGTGCTGCAAAGTGACAGACACATTGAACGGGGAGAGGGTCTCTTTTCCCGTGTGCACGTATGTGCCAG CTACATTGTGTGACCAAATGACTGGCATACTGGCAACAGATGTCAGTGCGGACGACGCGCAAAAACTGCT GGTTGGGCTCAACCAGCGTATAGTCGTCAACGGTCGCACCCAGAGAAACACCAATACCATGAAAAATTAC CTTTTGCCCGTAGTGGCCCAGGCATTTGCTAGGTGGGCAAAGGAATATAAGGAAGATCAAGAAGATGAAA GGCCACTAGGACTACGAGATAGACAGTTAGTCATGGGGTGTTGTTGGGCTTTTAGAAGGCACAAGATAAC ATCTATTTATAAGCGCCCGGATACCCAAACCATCATCAAAGTGAACAGCGATTTCCACTCATTCGTGCTG CCCAGGATAGGCAGTAACACATTGGAGATCGGGCTGAGAACAAGAATCAGGAAAATGTTAGAGGAGCACA AGGAGCCGTCACCTCTCATTACCGCCGAGGACGTACAAGAAGCTAAGTGCGCAGCCGATGAGGCTAAGGA GGTGCGTGAAGCCGAGGAGTTGCGCGCAGCTCTACCACCTTTGGCAGCTGATGTTGAGGAGCCCACTCTG GAAGCCGATGTAGACTTGATGTTACAAGAGGCTGGGGCCGGCTCAGTGGAGACACCTCGTGGCTTGATAA AGGTTACCAGCTACGATGGCGAGGACAAGATCGGCTCTTACGCTGTGCTTTCTCCGCAGGCTGTACTCAA GAGTGAAAAATTATCTTGCATCCACCCTCTCGCTGAACAAGTCATAGTGATAACACACTCTGGCCGAAAA GGGCGTTATGCCGTGGAACCATACCATGGTAAAGTAGTGGTGCCAGAGGGACATGCAATACCCGTCCAGG ACTTTCAAGCTCTGAGTGAAAGTGCCACCATTGTGTAC AACGAACGTGAGTTCGTAAACAGGTACCTGCA CCATATTGCCACACATGGAGGAGCGCTGAACACTGATGAAGAATATTACAAAACTGTCAAGCCCAGCGAG CACGACGGCGAATACCTGTACGACATCGACAGGAAACAGTGCGTCAAGAAAGAACTAGTCACTGGGCTAG GGCTCACAGGCGAGCTGGTGGATCCTCCCTTCCATGAATTCGCCTACGAGAGTCTGAGAACACGACCAGC CGCTCCTTACCAAGTACCAACCATAGGGGTGTATGGCGTGCCAGGATCAGGCAAGTCTGGCATCATTAAA AGCGCAGTCACCAAAAAAGATCTAGTGGTGAGCGCCAAGAAAGAAAACTGTGCAGAAATTATAAGGGACG TCAAGAAAATGAAAGGGCTGGACGTCAATGCCAGAACTGTGGACTCAGTGCTCTTGAATGGATGCAAACA CCCCGTAGAGACCCTGTATATTGACGAAGCTTTTGCTTGTCATGCAGGTACTCTCAGAGCGCTCATAGCC ATTATAAGACCTAAAAAGGCAGTGCTCTGCGGGGATCCCAAACAGTGCGGTTTTTTTAACATGATGTGCC TGAAAGTGCATTTTAACCACGAGATTTGCACACAAGTCTTCCACAAAAGCATCTCTCGCCGTTGCACTAA ATCTGTGACTTCGGTCGTCTCAACCTTGTTTTACGACAAAAAAATGAGAACGACGAATCCGAAAGAGACT AAGATTGTGATTGACACTACCGGCAGTACCAAACCTAAGCAGGACGATCTCATTCTCACTTGTTTCAGAG GGTGGGTGAAGCAGTTGCAAATAGATTACAAAGGCAACGAAATAATGACGGCAGCTGCCTCTCAAGGGCT GACCCGTAAAGGTGTGTATGCCGTTCGGTACAAGGTGAATGAAAATCCTCTGTACGCACCCACCTCAGAA CATGTGAACGTCCTACTGACCCGCACGGAGGACCGCATCGTGTG GAAAACACTAGCCGGCGACCCATGGA TAAAAACACTGACTGCCAAGTACCCTGGGAATTTCACTGCCACGATAGAGGAGTGGCAAGCAGAGCATGA TGCCATCATGAGGCACATCTTGGAGAGACCGGACCCTACCGACGTCTTCCAGAATAAGGCAAACGTGTGT TGGGCCAAGGCTTTAGTGCCGGTGCTGAAGACCGCTGGCATAGACATGACCACTGAACAATGGAACACTG TGGATTATTTTGAAACGGACAAAGCTCACTCAGCAGAGATAGTATTGAACCAACTATGCGTGAGGTTCTT TGGACTCGATCTGGACTCCGGTCTATTTTCTGCACCCACTGTTCCGTTATCCATTAGGAATAATCACTGG GATAACTCCCCGTCGCCTAACATGTACGGGCTGAATAAAGAAGTGGTCCGTCAGCTCTCTCGCAGGTACC CACAACTGCCTCGGGCAGTTGCCACTGGAAGAGTCTATGACATGAACACTGGTACACTGCGCAATTATGA TCCGCGCATAAACCTAGTACCTGTAAACAGAAGACTGCCTCATGCTTTAGTCCTCCACCATAATGAACAC CCACAGAGTGACTTTTCTTCATTCGTCAGCAAATTGAAGGGCAGAACTGTCCTGGTGGTCGGGGAAAAGT TGTCCGTCCCAGGCAAAATGGTTGACTGGTTGTCAGACCGGCCTGAGGCTACCTTCAGAGCTCGGCTGGA TTTAGGCATCCCAGGTGATGTGCCCAAATATGACATAATATTTGTTAATGTGAGGACCCCATATAAATAC CATCACTATCAGCAGTGTGAAGACCATGCCATTAAGCTTAGCATGTTGACCAAGAAAGCTTGTCTGCATC TGAATCCCGGCGGAACCTGTGTCAGCATAGGTTATGGTTACGCTGACAGGGCCAGCGAAAGCATCATTGG TGCTATAGCGCGGCAGTTCAAGTTTTCCCGGGTATGCAAACCGAAATCCT CACTTGAAGAGACGGAAGTT CTGTTTGTATTCATTGGGTACGATCGCAAGGCCCGTACGCACAATCCTTACAAGCTTTCATCAACCTTGA CCAACATTTATACAGGTTCCAGACTCCACGAAGCCGGATGTGCACCCTCATATCATGTGGTGCGAGGGGA TATTGCCACGGCCACCGAAGGAGTGATTATAAATGCTGCTAACAGCAAAGGACAACCTGGCGGAGGGGTG TGCGGAGCGCTGTATAAGAAATTCCCGGAAAGCTTCGATTTACAGCCGATCGAAGTAGGAAAAGCGCGAC TGGTCAAAGGTGCAGCTAAACATATCATTCATGCCGTAGGACCAAACTTCAACAAAGTTTCGGAGGTTGA AGGTGACAAACAGTTGGCAGAGGCTTATGAGTCCATCGCTAAGATTGTCAACGATAACAATTACAAGTCA GTAGCGATTCCACTGTTGTCCACCGGCATCTTTTCCGGGAACAAAGATCGACTAACCCAATCATTGAACC ATTTGCTGACAGCTTTAGACACCACTGATGCAGATGTAGCCATATACTGCAGGGACAAGAAATGGGAAAT GACTCTCAAGGAAGCAGTGGCTAGGAGAGAAGCAGTGGAGGAGATATGCATATCCGACGACTCTTCAGTG ACAGAACCTGATGCAGAGCTGGTGAGGGTGCATCCGAAGAGTTCTTTGGCTGGAAGGAAGGGCTACAGCA CAAGCGATGGCAAAACTTTCTCATATTTGGAAGGGACCAAGTTTCACCAGGCGGCCAAGGATATAGCAGA AATTAATGCCATGTGGCCCGTTGCAACGGAGGCCAATGAGCAGGTATGCATGTATATCCTCGGAGAAAGC ATGAGCAGTATTAGGTCGAAATGCCCCGTCGAAGAGTCGGAAGCCTCCACACCACCTAGCACGCTGCCTT GCTTGTGCATCCATGCCATGACTCCAGAAAGAGTACAGCGCCTAAAAGCCTCACGT CCAGAACAAATTAC TGTGTGCTCATCCTTTCCATTGCCGAAGTATAGAATCACTGGTGTGCAGAAGATCCAATGCTCCCAGCCT ATATTGTTCTCACCGAAAGTGCCTGCGTATATTCATCCAAGGAAGTATCTCGTGGAAACACCACCGGTAG ACGAGACTCCGGAGCCATCGGCAGAGAACCAATCCACAGAGGGGACACCTGAACAACCACCACTTATAAC CGAGGATGAGACCAGGACTAGAACGCCTGAGCCGATCATCATCGAAGAGGAAGAAGAGGATAGCATAAGT TTGCTGTCAGATGGCCCGACCCACCAGGTGCTGCAAGTCGAGGCAGACATTCACGGGCCGCCCTCTGTAT CTAGCTCATCCTGGTCCATTCCTCATGCATCCGACTTTGATGTGGACAGTTTATCCATACTTGACACCCT GGAGGGAGCTAGCGTGACCAGCGGGGCAACGTCAGCCGAGACTAACTCTTACTTCGCAAAGAGTATGGAG TTTCTGGCGCGACCGGTGCCTGCGCCTCGAACAGTATTCAGGAACCCTCCACATCCCGCTCCGCGCACAA GAACACCGTCACTTGCACCCAGCAGGGCCTGCTCGAGAACCAGCCTAGTTTCCACCCCGCCAGGCGTGAA TAGGGTGATCACTAGAGAGGAGCTCGAGGCGCTTACCCCGTCACGCACTCCTAGCAGGTCGGTCTCGAGA ACCAGCCTGGTCTCCAACCCGCCAGGCGTAAATAGGGTGATTACAAGAGAGGAGTTTGAGGCGTTCGTAG CACAACAACAATGACGGTTTGATGCGGGTGCATACATCTTTTCCTCCGACACCGGTCAAGGGCATTTACA ACAAAAATCAGTAAGGCAAACGGTGCTATCCGAAGTGGTGTTGGAGAGGACCGAATTGGAGATTTCGTAT GCCCCGCGCCTCGACCAAGAAAAAGAAGAATTACTACGCAAGAAATTACAGTTAAATCCCAC ACCTGCTA ACAGAAGCAGATACCAGTCCAGGAAGGTGGAGAACATGAAAGCCATAACAGCTAGACGTATTCTGCAAGG CCTAGGGCATTATTTGAAGGCAGAAGGAAAAGTGGAGTGCTACCGAACCCTGCATCCTGTTCCTTTGTAT TCATCTAGTGTGAACCGTGCCTTTTCAAGCCCCAAGGTCGCAGTGGAAGCCTGTAACGCCATGTTGAAAG AGAACTTTCCGACTGTGGCTTCTTACTGTATTATTCCAGAGTACGATGCCTATTTGGACATGGTTGACGG AGCTTCATGCTGCTTAGACACTGCCAGTTTTTGCCCTGCAAAGCTGCGCAGCTTTCCAAAGAAACACTCC TATTTGGAACCCACAATACGATCGGCAGTGCCTTCAGCGATCCAGAACACGCTCCAGAACGTCCTGGCAG CTGCCACAAAAAGAAATTGCAATGTCACGCAAATGAGAGAATTGCCCGTATTGGATTCGGCGGCCTTTAA TGTGGAATGCTTCAAGAAATATGCGTGTAATAATGAATATTGGGAAACGTTTAAAGAAAACCCCATCAGG CTTACTGAAGAAAACGTGGTAAATTACATTACCAAATTAAAAGGACCAAAAGCTGCTGCTCTTTTTGCGA AGACACATAATTTGAATATGTTGCAGGACATACCAATGGACAGGTTTGTAATGGACTTAAAGAGAGACGT GAAAGTGACTCCAGGAACAAAACATACTGAAGAACGGCCCAAGGTACAGGTGATCCAGGCTGCCGATCCG CTAGCAACAGCGTATCTGTGCGGAATCCACCGAGAGCTGGTTAGGAGATTAAATGCGGTCCTGCTTCCGA ACATTCATACACTGTTTGATATGTCGGCTGAAGACTTTGACGCTATTATAGCCGAGCACTTCCAGCCTGG GGATTGTGTTCTGGAAACTGACATCGCGTCGTTTGATAAAAGTGAGGACGACGCCATGGCTCTGACCG CG TTAATGATTCTGGAAGACTTAGGTGTGGACGCAGAGCTGTTGACGCTGATTGAGGCGGCTTTCGGCGAAA TTTCATCAATACATTTGCCCACTAAAACTAAATTTAAATTCGGAGCCATGATGAAATCTGGAATGTTCCT CACACTGTTTGTGAACACAGTCATTAACATTGTAATCGCAAGCAGAGTGTTGAGAGAACGGCTAACCGGA TCACCATGTGCAGCATTCATTGGAGATGACAATATCGTGAAAGGAGTCAAATCGGACAAATTAATGGCAG ACAGGTGCGCCACCTGGTTGAATATGGAAGTCAAGATTATAGATGCTGTGGTGGGCGAGAAAGCGCCTTA TTTCTGTGGAGGGTTTATTTTGTGTGACTCCGTGACCGGCACAGCGTGCCGTGTGGCAGACCCCCTAAAA AGGCTGTTTAAGCTTGGCAAACCTCTGGCAGCAGACGATGAACATGATGATGACAGGAGAAGGGCATTGC ATGAAGAGTCAACACGCTGGAACCGAGTGGGTATTCTTTCAGAGCTGTGCAAGGCAGTAGAATCAAGGTA TGAAACCGTAGGAACTTCCATCATAGTTATGGCCATGACTACTCTAGCTAGCAGTGTTAAATCATTCAGC TACCTGAGAGGGGCCCCTATAACTCTCTACGGCTAACCTGAATGGACTACGACATAGTCTAGTCCGCCAA GATGAGGCCTGGCCTGCCCTCCTACCTGATCATCCTGGCCGTGTGCCTGTTCAGCCACCTGCTGTCCAGC AGATACGGCGCCGAGGCCGTGAGCGAGCCCCTGGACAAGGCTTTCCACCTGCTGCTGAACACCTACGGCA GACCCATCCGGTTTCTGCGGGAGAACACCACCCAGTGCACCTACAACAGCAGCCTGCGGAACAGCACCGT CGTGAGAGAGAACGCCATCAGCTTCAACTTTTTCCAGAGCTACAACCAGTACTACGTGTTCCACATGCCC AGA TGCCTGTTTGCCGGCCCTCTGGCCGAGCAGTTCCTGAACCAGGTGGACCTGACCGAGACACTGGAAA GATACCAGCAGCGGCTGAATACCTACGCCCTGGTGTCCAAGGACCTGGCCAGCTACCGGTCCTTTAGCCA GCAGCTCAAGGCTCAGGATAGCCTCGGCGAGCAGCCTACCACCGTGCCCCCTCCCATCGACCTGAGCATC CCCCACGTGTGGATGCCTCCCCAGACCACCCCTCACGGCTGGACCGAGAGCCACACCACCTCCGGCCTGC ACAGACCCCACTTCAACCAGACCTGCATCCTGTTCGACGGCCACGACCTGCTGTTTAGCACCGTGACCCC CTGCCTGCACCAGGGCTTCTACCTGATCGACGAGCTGAGATACGTGAAGATCACCCTGACCGAGGATTTC TTCGTGGTCACCGTGTCCATCGACGACGACACCCCCATGCTGCTGATCTTCGGCCACCTGCCCAGAGTGC TGTTCAAGGCCCCCTACCAGCGGGACAACTTCATCCTGCGGCAGACCGAGAAGCACGAGCTGCTGGTGCT GGTCAAGAAGGACCAGCTGAACCGGCACTCCTACCTGAAGGACCCCGACTTCCTGGACGCCGCCCTGGAC TTCAACTACCTGGACCTGAGCGCCCTGCTGAGAAACAGCTTCCACAGATACGCCGTGGACGTGCTGAAGT CCGGACGGTGCCAGATGCTCGATCGGCGGACCGTGGAGATGGCCTTCGCCTATGCCCTCGCCCTGTTCGC CGCTGCCAGACAGGAAGAGGCTGGCGCCCAGGTGTCAGTGCCCAGAGCCCTGGATAGACAGGCCGCCCTG CTGCAGATCCAGGAATTCATGATCACCTGCCTGAGCCAGACCCCCCCTAGAACCACCCTGCTGCTGTACC CCACAGCCGTGGATCTGGCCAAGAGGGCCCTGTGGACCCCCAACCAGATCACCGACATCACAAGCCTCGT GCGGCTCGT GTACATCCTGAGCAAGCAGAACCAGCAGCACCTGATCCCCCAGTGGGCCCTGAGACAGATC GCCGACTTCGCCCTGAAGCTGCACAAGACCCATCTGGCCAGCTTTCTGAGCGCCTTCGCCAGGCAGGAAC TGTACCTGATGGGCAGCCTGGTCCACAGCATGCTGGTGCATACCACCGAGCGGCGGGAGATCTTCATCGT GGAGACAGGCCTGTGTAGCCTGGCCGAGCTGTCCCACTTTACCCAGCTGCTGGCCCACCCTCACCACGAG TACCTGAGCGACCTGTACACCCCCTGCAGCAGCAGCGGCAGACGGGACCACAGCCTGGAACGGCTGACCA GACTGTTCCCCGATGCCACCGTGCCTGCTACAGTGCCTGCCGCCCTGTCCATCCTGTCCACCATGCAGCC CAGCACCCTGGAAACCTTCCCCGACCTGTTCTGCCTGCCCCTGGGCGAGAGCTTTAGCGCCCTGACCGTG TCCGAGCACGTGTCCTACATCGTGACCAATCAGTACCTGATCAAGGGCATCAGCTACCCCGTGTCCACCA CAGTCGTGGGCCAGAGCCTGATCATCACCCAGACCGACAGCCAGACCAAGTGCGAGCTGACCCGGAACAT GCACACCACACACAGCATCACCGTGGCCCTGAACATCAGCCTGGAAAACTGCGCTTTCTGTCAGTCTGCC CTGCTGGAATACGACGATACCCAGGGCGTGATCAACATCATGTACATGCACGACAGCGACGACGTGCTGT TCGCCCTGGACCCCTACAACGAGGTGGTGGTGTCCAGCCCCCGGACCCACTACCTGATGCTGCTGAAGAA CGGCACCGTGCTGGAAGTGACCGACGTGGTGGTGGACGCCACCGACAGCAGACTGCTGATGATGAGCGTG TACGCCCTGAGCGCCATCATCGGCATCTACCTGCTGTACCGGATGCTGAAAACCTGCTGATAATCTAGAG GCCCCTATAACTCTC TACGGCTAACCTGAATGGACTACGACATAGTCTAGTCCGCCAAGATGTGCAGAAG GCCCGACTGCGGCTTCAGCTTCAGCCCTGGACCCGTGATCCTGCTGTGGTGCTGCCTGCTGCTGCCTATC GTGTCCTCTGCCGCCGTGTCTGTGGCCCCTACAGCCGCCGAGAAGGTGCCAGCCGAGTGCCCCGAGCTGA CCAGAAGATGCCTGCTGGGCGAGGTGTTCGAGGGCGACAAGTACGAGAGCTGGCTGCGGCCCCTGGTCAA CGTGACCGGCAGAGATGGCCCCCTGAGCCAGCTGATCCGGTACAGACCCGTGACCCCCGAGGCCGCCAAT AGCGTGCTGCTGGACGAGGCCTTCCTGGATACCCTGGCCCTGCTGTACAACAACCCCGACCAGCTGAGAG CCCTGCTGACCCTGCTGTCCAGCGACACCGCCCCCAGATGGATGACCGTGATGCGGGGCTACAGCGAGTG TGGAGATGGCAGCCCTGCCGTGTACACCTGCGTGGACGACCTGTGCAGAGGCTACGACCTGACCAGACTG AGCTACGGCCGGTCCATCTTCACAGAGCACGTGCTGGGCTTCGAGCTGGTGCCCCCCAGCCTGTTCAACG TGGTGGTGGCCATCCGGAACGAGGCCACCAGAACCAACAGAGCCGTGCGGCTGCCTGTGTCTACAGCCGC TGCACCTGAGGGCATCACACTGTTCTACGGCCTGTACAACGCCGTGAAAGAGTTCTGCCTCCGGCACCAG CTGGATCCCCCCCTGCTGAGACACCTGGACAAGTACTACGCCGGCCTGCCCCCAGAGCTGAAGCAGACCA GAGTGAACCTGCCCGCCCACAGCAGATATGGCCCTCAGGCCGTGGACGCCAGATGATAACGCCGGCGGCC CCTATAACTCTCTACGGCTAACCTGAATGGACTACGACATAGTCTAGTCCGCCAAGATGAGCCCCAAGGA CCTGACCCCCTTCCTGACAAC CCTGTGGCTGCTCCTGGGCCATAGCAGAGTGCCTAGAGTGCGGGCCGAG GAATGCTGCGAGTTCATCAACGTGAACCACCCCCCCGAGCGGTGCTACGACTTCAAGATGTGCAACCGGT TCACCGTGGCCCTGAGATGCCCCGACGGCGAAGTGTGCTACAGCCCCGAGAAAACCGCCGAGATCCGGGG CATCGTGACCACCATGACCCACAGCCTGACCCGGCAGGTGGTGCACAACAAGCTGACCAGCTGCAACTAC AACCCCCTGTACCTGGAAGCCGACGGCCGGATCAGATGCGGCAAAGTGAACGACAAGGCCCAGTACCTGC TGGGAGCCGCCGGAAGCGTGCCCTACCGGTGGATCAACCTGGAATACGACAAGATCACCCGGATCGTGGG CCTGGACCAGTACCTGGAAAGCGTGAAGAAGCACAAGCGGCTGGACGTGTGCAGAGCCAAGATGGGCTAC ATGCTGCAGCTGTTGAATTTTGACCTTCTTAAGCTTGCGGGAGACGTCGAGTCCAACCCCGGGCCCATGC TGCGGCTGCTGCTGAGACACCACTTCCACTGCCTGCTGCTGTGTGCCGTGTGGGCCACCCCTTGTCTGGC CAGCCCTTGGAGCACCCTGACCGCCAACCAGAACCCTAGCCCCCCTTGGTCCAAGCTGACCTACAGCAAG CCCCACGACGCCGCCACCTTCTACTGCCCCTTTCTGTACCCCAGCCCTCCCAGAAGCCCCCTGCAGTTCA GCGGCTTCCAGAGAGTGTCCACCGGCCCTGAGTGCCGGAACGAGACACTGTACCTGCTGTACAACCGGGA GGGCCAGACACTGGTGGAGCGGAGCAGCACCTGGGTGAAAAAAGTGATCTGGTATCTGAGCGGCCGGAAC CAGACCATCCTGCAGCGGATGCCCAGAACCGCCAGCAAGCCCAGCGACGGCAACGTGCAGATCAGCGTGG AGGACGCCAAAATCTTCGGCGCCCACA TGGTGCCCAAGCAGACCAAGCTGCTGAGATTCGTGGTCAACGA CGGCACCAGATATCAGATGTGCGTGATGAAGCTGGAAAGCTGGGCCCACGTGTTCCGGGACTACTCCGTG AGCTTCCAGGTCCGGCTGACCTTCACCGAGGCCAACAACCAGACCTACACCTTCTGCACCCACCCCAACC TGATCGTGCTGCTGAACTTCGACCTGCTGAAGCTGGCCGGCGACGTGGAGAGCAACCCCGGCCCCCATAT GCGGCTGTGCAGAGTGTGGCTGTCCGTGTGCCTGTGTGCCGTGGTGCTGGGCCAGTGCCAGAGAGAGACA GCCGAGAAGAACGACTACTACCGGGTGCCCCACTACTGGGATGCCTGCAGCAGAGCCCTGCCCGACCAGA CCCGGTACAAATACGTGGAGCAGCTCGTGGACCTGACCCTGAACTACCACTACGACGCCAGCCACGGCCT GGACAACTTCGACGTGCTGAAGCGGATCAACGTGACCGAGGTGTCCCTGCTGATCAGCGACTTCCGGCGG CAGAACAGAAGAGGCGGCACCAACAAGCGGACCACCTTCAACGCCGCTGGCTCTCTGGCCCCTCACGCCA GATCCCTGGAATTCAGCGTGCGGCTGTTCGCCAACTGATAACGTTGCATCCTGCAGGATACAGCAGCAAT TGGCAAGCTGCTTACATAGAACTCGCGGCGATTGGCATGCCGCCTTAAAATTTTTATTTTATTTTTCTTT TCTTTTCCGAATCGGATTTTGTTTTTAATATTTCAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAG GGTCGGCATGGCATCTCCACCTCCTCGCGGTCCGACCTGGGCATCCGAAGGAGGACGCACGTCCACTCGG ATGGCTAAGGGAGAGCCACGTTTAAACGCTAGAGCAAGACGTTTCCCGTTGAATATGGCTCATAACACCC CTTGTATTACTGTTTATGTAAGCAGACAGTTTT ATTGTTCATGATGATATATTTTTATCTTGTGCAATGT AACATCAGAGATTTTGAGACACAACGTGGCTTTGTTGAATAAATCGAACTTTTGCTGAGTTGAAGGATCA GATCACGCATCTTCCCGACAACGCAGACCGTTCCGTGGCAAAGCAAAAGTTCAAAATCACCAACTGGTCC ACCTACAACAAAGCTCTCATCAACCGTGGCTCCCTCACTTTCTGGCTGGATGATGGGGCGATTCAGGCCT GGTATGAGTCAGCAACACCTTCTTCACGAGGCAGACCTCAGCGCTAGCGGAGTGTATACTGGCTTACTAT GTTGGCACTGATGAGGGTGTCAGTGAAGTGCTTCATGTGGCAGGAGAAAAAAGGCTGCACCGGTGCGTCA GCAGAATATGTGATACAGGATATATTCCGCTTCCTCGCTCACTGACTCGCTACGCTCGGTCGTTCGACTG CGGCGAGCGGAAATGGCTTACGAACGGGGCGGAGATTTCCTGGAAGATGCCAGGAAGATACTTAACAGGG AAGTGAGAGGGCCGCGGCAAAGCCGTTTTTCCATAGGCTCCGCCCCCCTGACAAGCATCACGAAATCTGA CGCTCAAATCAGTGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCTGGCGGCTCCCT CGTGCGCTCTCCTGTTCCTGCCTTTCGGTTTACCGGTGTCATTCCGCTGTTATGGCCGCGTTTGTCTCAT TCCACGCCTGACACTCAGTTCCGGGTAGGCAGTTCGCTCCAAGCTGGACTGTATGCACGAACCCCCCGTT CAGTCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGAAAGACATGCAAAAGCAC CACTGGCAGCAGCCACTGGTAATTGATTTAGAGGAGTTAGTCTTGAAGTCATGCGCCGGTTAAGGCTAAA CTGAAAGGACAAGTTTTGGTGACTGCGCTCCTCCAAGCC AGTTACCTCGGTTCAAAGAGTTGGTAGCTCA GAGAACCTTCGAAAAACCGCCCTGCAAGGCGGTTTTTTCGTTTTCAGAGCAAGAGATTACGCGCAGACCA AAACGATCTCAAGAAGATCATCTTATTAAGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGA TTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATC AATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTATTAGAAAAATTCATCCAGCAGACGATAAAAC GCAATACGCTGGCTATCCGGTGCCGCAATGCCATACAGCACCAGAAAACGATCCGCCCATTCGCCGCCCA GTTCTTCCGCAATATCACGGGTGGCCAGCGCAATATCCTGATAACGATCCGCCACGCCCAGACGGCCGCA ATCAATAAAGCCGCTAAAACGGCCATTTTCCACCATAATGTTCGGCAGGCACGCATCACCATGGGTCACC ACCAGATCTTCGCCATCCGGCATGCTCGCTTTCAGACGCGCAAACAGCTCTGCCGGTGCCAGGCCCTGAT GTTCTTCATCCAGATCATCCTGATCCACCAGGCCCGCTTCCATACGGGTACGCGCACGTTCAATACGATG TTTCGCCTGATGATCAAACGGACAGGTCGCCGGGTCCAGGGTATGCAGACGACGCATGGCATCCGCCATA ATGCTCACTTTTTCTGCCGGCGCCAGATGGCTAGACAGCAGATCCTGACCCGGCACTTCGCCCAGCAGCA GCCAATCACGGCCCGCTTCGGTCACCACATCCAGCACCGCCGCACACGGAACACCGGTGGTGGCCAGCCA GCTCAGACGCGCCGCTTCATCCTGCAGCTCGTTCAGCGCACCGCTCAGATCGGTTTTCACAAACAGCACC GGACGACCCTGCGCGCTCAGACGAAACACCGCCGCATCAGAGCAG CCAATGGTCTGCTGCGCCCAATCAT AGCCAAACAGACGTTCCACCCACGCTGCCGGGCTACCCGCATGCAGGCCATCCTGTTCAATCATACTCTT CCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATT TAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTAAATTGTAAGCGTTAA TATTTTGTTAAAATTCGCGTTAAATTTTTGTTAAATCAGCTCATTTTTTAACCAATAGGCCGAAATCGGC AAAATCCCTTATAAATCAAAAGAATAGACCGAGATAGGGTTGAGTGGCCGCTACAGGGCGCTCCCATTCG CCATTCAGGCTGCGCAACTGTTGGGAAGGGCGTTTCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCG AAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACACGCGTAATACG ACTCACTATAG Vector A527: SGP-gH-gL-SGP-SGP-EMCV-UL128-UL130-UL131-EV71 ATAGGCGGCGCATGAGAGAAGCCCAGACCAATTACCTACCCAAAATGGAGAAAGTTCACGTTGACATCGA GGAAGACAGCCCATTCCTCAGAGCTTTGCAGCGGAGCTTCCCGCAGTTTGAGGTAGAAGCCAAGCAGGTC ACTGATAATGACCATGCTAATGCCAGAGCGTTTTCGCATCTGGCTTCAAAACTGATCGAAACGGAGGTGG ACCCATCCGACACGATCCTTGACATTGGAAGTGCGCCCGCCCGCAGAATGTATTCTAAGCACAAGTATCA TTGTATCTGTCCGATGAGATGTGCGGAAGATCCGGACAGATTGTATAAGTATGCAACTAAGCTGAAGAAA AACTGTAAGGAAATAACTGATAAGGAATTGGACAAGAAAATGAAGGAGCTCGCCGCCGTCATGAGCGACC CTGACCTGGAAACTGAGACTATGTGCCTCCACGACGACGAGTCGTGTCGCTACGAAGGGCAAGTCGCTGT TTACCAGGATGTATACGCGGTTGACGGACCGACAAGTCTCTATCACCAAGCCAATAAGGGAGTTAGAGTC GCCTACTGGATAGGCTTTGACACCACCCCTTTTATGTTTAAGAACTTGGCTGGAGCATATCCATCATACT CTACCAACTGGGCCGACGAAACCGTGTTAACGGCTCGTAACATAGGCCTATGCAGCTCTGACGTTATGGA GCGGTCACGTAGAGGGATGTCCATTCTTAGAAAGAAGTATTTGAAACCATCCAACAATGTTCTATTCTCT GTTGGCTCGACCATCTACCACGAGAAGAGGGACTTACTGAGGAGCTGGCACCTGCCGTCTGTATTTCACT TACGTGGCAAGCAAAATTACACATGTCGGTGTGAGACTATAGTTAGTTGCGACGGGTACGTCGTTAAAAG AATAGCTATCAGTCCAGGCCTGTATGGGAAG CCTTCAGGCTATGCTGCTACGATGCACCGCGAGGGATTC TTGTGCTGCAAAGTGACAGACACATTGAACGGGGAGAGGGTCTCTTTTCCCGTGTGCACGTATGTGCCAG CTACATTGTGTGACCAAATGACTGGCATACTGGCAACAGATGTCAGTGCGGACGACGCGCAAAAACTGCT GGTTGGGCTCAACCAGCGTATAGTCGTCAACGGTCGCACCCAGAGAAACACCAATACCATGAAAAATTAC CTTTTGCCCGTAGTGGCCCAGGCATTTGCTAGGTGGGCAAAGGAATATAAGGAAGATCAAGAAGATGAAA GGCCACTAGGACTACGAGATAGACAGTTAGTCATGGGGTGTTGTTGGGCTTTTAGAAGGCACAAGATAAC ATCTATTTATAAGCGCCCGGATACCCAAACCATCATCAAAGTGAACAGCGATTTCCACTCATTCGTGCTG CCCAGGATAGGCAGTAACACATTGGAGATCGGGCTGAGAACAAGAATCAGGAAAATGTTAGAGGAGCACA AGGAGCCGTCACCTCTCATTACCGCCGAGGACGTACAAGAAGCTAAGTGCGCAGCCGATGAGGCTAAGGA GGTGCGTGAAGCCGAGGAGTTGCGCGCAGCTCTACCACCTTTGGCAGCTGATGTTGAGGAGCCCACTCTG GAAGCCGATGTAGACTTGATGTTACAAGAGGCTGGGGCCGGCTCAGTGGAGACACCTCGTGGCTTGATAA AGGTTACCAGCTACGATGGCGAGGACAAGATCGGCTCTTACGCTGTGCTTTCTCCGCAGGCTGTACTCAA GAGTGAAAAATTATCTTGCATCCACCCTCTCGCTGAACAAGTCATAGTGATAACACACTCTGGCCGAAAA GGGCGTTATGCCGTGGAACCATACCATGGTAAAGTAGTGGTGCCAGAGGGACATGCAATACCCGTCCAGG ACTTTCAAGCTCTGAGTGAAAGTGCCACCATTGTGTA CAACGAACGTGAGTTCGTAAACAGGTACCTGCA CCATATTGCCACACATGGAGGAGCGCTGAACACTGATGAAGAATATTACAAAACTGTCAAGCCCAGCGAG CACGACGGCGAATACCTGTACGACATCGACAGGAAACAGTGCGTCAAGAAAGAACTAGTCACTGGGCTAG GGCTCACAGGCGAGCTGGTGGATCCTCCCTTCCATGAATTCGCCTACGAGAGTCTGAGAACACGACCAGC CGCTCCTTACCAAGTACCAACCATAGGGGTGTATGGCGTGCCAGGATCAGGCAAGTCTGGCATCATTAAA AGCGCAGTCACCAAAAAAGATCTAGTGGTGAGCGCCAAGAAAGAAAACTGTGCAGAAATTATAAGGGACG TCAAGAAAATGAAAGGGCTGGACGTCAATGCCAGAACTGTGGACTCAGTGCTCTTGAATGGATGCAAACA CCCCGTAGAGACCCTGTATATTGACGAAGCTTTTGCTTGTCATGCAGGTACTCTCAGAGCGCTCATAGCC ATTATAAGACCTAAAAAGGCAGTGCTCTGCGGGGATCCCAAACAGTGCGGTTTTTTTAACATGATGTGCC TGAAAGTGCATTTTAACCACGAGATTTGCACACAAGTCTTCCACAAAAGCATCTCTCGCCGTTGCACTAA ATCTGTGACTTCGGTCGTCTCAACCTTGTTTTACGACAAAAAAATGAGAACGACGAATCCGAAAGAGACT AAGATTGTGATTGACACTACCGGCAGTACCAAACCTAAGCAGGACGATCTCATTCTCACTTGTTTCAGAG GGTGGGTGAAGCAGTTGCAAATAGATTACAAAGGCAACGAAATAATGACGGCAGCTGCCTCTCAAGGGCT GACCCGTAAAGGTGTGTATGCCGTTCGGTACAAGGTGAATGAAAATCCTCTGTACGCACCCACCTCAGAA CATGTGAACGTCCTACTGACCCGCACGGAGGACCGCATCGTGT GGAAAACACTAGCCGGCGACCCATGGA TAAAAACACTGACTGCCAAGTACCCTGGGAATTTCACTGCCACGATAGAGGAGTGGCAAGCAGAGCATGA TGCCATCATGAGGCACATCTTGGAGAGACCGGACCCTACCGACGTCTTCCAGAATAAGGCAAACGTGTGT TGGGCCAAGGCTTTAGTGCCGGTGCTGAAGACCGCTGGCATAGACATGACCACTGAACAATGGAACACTG TGGATTATTTTGAAACGGACAAAGCTCACTCAGCAGAGATAGTATTGAACCAACTATGCGTGAGGTTCTT TGGACTCGATCTGGACTCCGGTCTATTTTCTGCACCCACTGTTCCGTTATCCATTAGGAATAATCACTGG GATAACTCCCCGTCGCCTAACATGTACGGGCTGAATAAAGAAGTGGTCCGTCAGCTCTCTCGCAGGTACC CACAACTGCCTCGGGCAGTTGCCACTGGAAGAGTCTATGACATGAACACTGGTACACTGCGCAATTATGA TCCGCGCATAAACCTAGTACCTGTAAACAGAAGACTGCCTCATGCTTTAGTCCTCCACCATAATGAACAC CCACAGAGTGACTTTTCTTCATTCGTCAGCAAATTGAAGGGCAGAACTGTCCTGGTGGTCGGGGAAAAGT TGTCCGTCCCAGGCAAAATGGTTGACTGGTTGTCAGACCGGCCTGAGGCTACCTTCAGAGCTCGGCTGGA TTTAGGCATCCCAGGTGATGTGCCCAAATATGACATAATATTTGTTAATGTGAGGACCCCATATAAATAC CATCACTATCAGCAGTGTGAAGACCATGCCATTAAGCTTAGCATGTTGACCAAGAAAGCTTGTCTGCATC TGAATCCCGGCGGAACCTGTGTCAGCATAGGTTATGGTTACGCTGACAGGGCCAGCGAAAGCATCATTGG TGCTATAGCGCGGCAGTTCAAGTTTTCCCGGGTATGCAAACCGAAATCC TCACTTGAAGAGACGGAAGTT CTGTTTGTATTCATTGGGTACGATCGCAAGGCCCGTACGCACAATCCTTACAAGCTTTCATCAACCTTGA CCAACATTTATACAGGTTCCAGACTCCACGAAGCCGGATGTGCACCCTCATATCATGTGGTGCGAGGGGA TATTGCCACGGCCACCGAAGGAGTGATTATAAATGCTGCTAACAGCAAAGGACAACCTGGCGGAGGGGTG TGCGGAGCGCTGTATAAGAAATTCCCGGAAAGCTTCGATTTACAGCCGATCGAAGTAGGAAAAGCGCGAC TGGTCAAAGGTGCAGCTAAACATATCATTCATGCCGTAGGACCAAACTTCAACAAAGTTTCGGAGGTTGA AGGTGACAAACAGTTGGCAGAGGCTTATGAGTCCATCGCTAAGATTGTCAACGATAACAATTACAAGTCA GTAGCGATTCCACTGTTGTCCACCGGCATCTTTTCCGGGAACAAAGATCGACTAACCCAATCATTGAACC ATTTGCTGACAGCTTTAGACACCACTGATGCAGATGTAGCCATATACTGCAGGGACAAGAAATGGGAAAT GACTCTCAAGGAAGCAGTGGCTAGGAGAGAAGCAGTGGAGGAGATATGCATATCCGACGACTCTTCAGTG ACAGAACCTGATGCAGAGCTGGTGAGGGTGCATCCGAAGAGTTCTTTGGCTGGAAGGAAGGGCTACAGCA CAAGCGATGGCAAAACTTTCTCATATTTGGAAGGGACCAAGTTTCACCAGGCGGCCAAGGATATAGCAGA AATTAATGCCATGTGGCCCGTTGCAACGGAGGCCAATGAGCAGGTATGCATGTATATCCTCGGAGAAAGC ATGAGCAGTATTAGGTCGAAATGCCCCGTCGAAGAGTCGGAAGCCTCCACACCACCTAGCACGCTGCCTT GCTTGTGCATCCATGCCATGACTCCAGAAAGAGTACAGCGCCTAAAAGCCTCACG TCCAGAACAAATTAC TGTGTGCTCATCCTTTCCATTGCCGAAGTATAGAATCACTGGTGTGCAGAAGATCCAATGCTCCCAGCCT ATATTGTTCTCACCGAAAGTGCCTGCGTATATTCATCCAAGGAAGTATCTCGTGGAAACACCACCGGTAG ACGAGACTCCGGAGCCATCGGCAGAGAACCAATCCACAGAGGGGACACCTGAACAACCACCACTTATAAC CGAGGATGAGACCAGGACTAGAACGCCTGAGCCGATCATCATCGAAGAGGAAGAAGAGGATAGCATAAGT TTGCTGTCAGATGGCCCGACCCACCAGGTGCTGCAAGTCGAGGCAGACATTCACGGGCCGCCCTCTGTAT CTAGCTCATCCTGGTCCATTCCTCATGCATCCGACTTTGATGTGGACAGTTTATCCATACTTGACACCCT GGAGGGAGCTAGCGTGACCAGCGGGGCAACGTCAGCCGAGACTAACTCTTACTTCGCAAAGAGTATGGAG TTTCTGGCGCGACCGGTGCCTGCGCCTCGAACAGTATTCAGGAACCCTCCACATCCCGCTCCGCGCACAA GAACACCGTCACTTGCACCCAGCAGGGCCTGCTCGAGAACCAGCCTAGTTTCCACCCCGCCAGGCGTGAA TAGGGTGATCACTAGAGAGGAGCTCGAGGCGCTTACCCCGTCACGCACTCCTAGCAGGTCGGTCTCGAGA ACCAGCCTGGTCTCCAACCCGCCAGGCGTAAATAGGGTGATTACAAGAGAGGAGTTTGAGGCGTTCGTAG CACAACAACAATGACGGTTTGATGCGGGTGCATACATCTTTTCCTCCGACACCGGTCAAGGGCATTTACA ACAAAAATCAGTAAGGCAAACGGTGCTATCCGAAGTGGTGTTGGAGAGGACCGAATTGGAGATTTCGTAT GCCCCGCGCCTCGACCAAGAAAAAGAAGAATTACTACGCAAGAAATTACAGTTAAATCCCA CACCTGCTA ACAGAAGCAGATACCAGTCCAGGAAGGTGGAGAACATGAAAGCCATAACAGCTAGACGTATTCTGCAAGG CCTAGGGCATTATTTGAAGGCAGAAGGAAAAGTGGAGTGCTACCGAACCCTGCATCCTGTTCCTTTGTAT TCATCTAGTGTGAACCGTGCCTTTTCAAGCCCCAAGGTCGCAGTGGAAGCCTGTAACGCCATGTTGAAAG AGAACTTTCCGACTGTGGCTTCTTACTGTATTATTCCAGAGTACGATGCCTATTTGGACATGGTTGACGG AGCTTCATGCTGCTTAGACACTGCCAGTTTTTGCCCTGCAAAGCTGCGCAGCTTTCCAAAGAAACACTCC TATTTGGAACCCACAATACGATCGGCAGTGCCTTCAGCGATCCAGAACACGCTCCAGAACGTCCTGGCAG CTGCCACAAAAAGAAATTGCAATGTCACGCAAATGAGAGAATTGCCCGTATTGGATTCGGCGGCCTTTAA TGTGGAATGCTTCAAGAAATATGCGTGTAATAATGAATATTGGGAAACGTTTAAAGAAAACCCCATCAGG CTTACTGAAGAAAACGTGGTAAATTACATTACCAAATTAAAAGGACCAAAAGCTGCTGCTCTTTTTGCGA AGACACATAATTTGAATATGTTGCAGGACATACCAATGGACAGGTTTGTAATGGACTTAAAGAGAGACGT GAAAGTGACTCCAGGAACAAAACATACTGAAGAACGGCCCAAGGTACAGGTGATCCAGGCTGCCGATCCG CTAGCAACAGCGTATCTGTGCGGAATCCACCGAGAGCTGGTTAGGAGATTAAATGCGGTCCTGCTTCCGA ACATTCATACACTGTTTGATATGTCGGCTGAAGACTTTGACGCTATTATAGCCGAGCACTTCCAGCCTGG GGATTGTGTTCTGGAAACTGACATCGCGTCGTTTGATAAAAGTGAGGACGACGCCATGGCTCTGACC GCG TTAATGATTCTGGAAGACTTAGGTGTGGACGCAGAGCTGTTGACGCTGATTGAGGCGGCTTTCGGCGAAA TTTCATCAATACATTTGCCCACTAAAACTAAATTTAAATTCGGAGCCATGATGAAATCTGGAATGTTCCT CACACTGTTTGTGAACACAGTCATTAACATTGTAATCGCAAGCAGAGTGTTGAGAGAACGGCTAACCGGA TCACCATGTGCAGCATTCATTGGAGATGACAATATCGTGAAAGGAGTCAAATCGGACAAATTAATGGCAG ACAGGTGCGCCACCTGGTTGAATATGGAAGTCAAGATTATAGATGCTGTGGTGGGCGAGAAAGCGCCTTA TTTCTGTGGAGGGTTTATTTTGTGTGACTCCGTGACCGGCACAGCGTGCCGTGTGGCAGACCCCCTAAAA AGGCTGTTTAAGCTTGGCAAACCTCTGGCAGCAGACGATGAACATGATGATGACAGGAGAAGGGCATTGC ATGAAGAGTCAACACGCTGGAACCGAGTGGGTATTCTTTCAGAGCTGTGCAAGGCAGTAGAATCAAGGTA TGAAACCGTAGGAACTTCCATCATAGTTATGGCCATGACTACTCTAGCTAGCAGTGTTAAATCATTCAGC TACCTGAGAGGGGCCCCTATAACTCTCTACGGCTAACCTGAATGGACTACGACATAGTCTAGTCCGCCAA GATGAGGCCTGGCCTGCCCTCCTACCTGATCATCCTGGCCGTGTGCCTGTTCAGCCACCTGCTGTCCAGC AGATACGGCGCCGAGGCCGTGAGCGAGCCCCTGGACAAGGCTTTCCACCTGCTGCTGAACACCTACGGCA GACCCATCCGGTTTCTGCGGGAGAACACCACCCAGTGCACCTACAACAGCAGCCTGCGGAACAGCACCGT AG CGTGAGAGAGAACGCCATCAGCTTCAACTTTTTCCAGAGCTACAACCAGTACTACGTGTTCCACATGCCC ATGCCTGTTTGCCGGCCCTCTGGCCGAGCAGTTCCTGAACCAGGTGGACCTGACCGAGACACTGGAAA GATACCAGCAGCGGCTGAATACCTACGCCCTGGTGTCCAAGGACCTGGCCAGCTACCGGTCCTTTAGCCA GCAGCTCAAGGCTCAGGATAGCCTCGGCGAGCAGCCTACCACCGTGCCCCCTCCCATCGACCTGAGCATC CCCCACGTGTGGATGCCTCCCCAGACCACCCCTCACGGCTGGACCGAGAGCCACACCACCTCCGGCCTGC ACAGACCCCACTTCAACCAGACCTGCATCCTGTTCGACGGCCACGACCTGCTGTTTAGCACCGTGACCCC CTGCCTGCACCAGGGCTTCTACCTGATCGACGAGCTGAGATACGTGAAGATCACCCTGACCGAGGATTTC TTCGTGGTCACCGTGTCCATCGACGACGACACCCCCATGCTGCTGATCTTCGGCCACCTGCCCAGAGTGC TGTTCAAGGCCCCCTACCAGCGGGACAACTTCATCCTGCGGCAGACCGAGAAGCACGAGCTGCTGGTGCT GGTCAAGAAGGACCAGCTGAACCGGCACTCCTACCTGAAGGACCCCGACTTCCTGGACGCCGCCCTGGAC TTCAACTACCTGGACCTGAGCGCCCTGCTGAGAAACAGCTTCCACAGATACGCCGTGGACGTGCTGAAGT CCGGACGGTGCCAGATGCTCGATCGGCGGACCGTGGAGATGGCCTTCGCCTATGCCCTCGCCCTGTTCGC CGCTGCCAGACAGGAAGAGGCTGGCGCCCAGGTGTCAGTGCCCAGAGCCCTGGATAGACAGGCCGCCCTG CTGCAGATCCAGGAATTCATGATCACCTGCCTGAGCCAGACCCCCCCTAGAACCACCCTGCTGCTGTACC CCACAGCCGTGGATCTGGCCAAGAGGGCCCTGTGGACCCCCAACCAGATCACCGACATCACAAGCCTCGT GCGGCTCG TGTACATCCTGAGCAAGCAGAACCAGCAGCACCTGATCCCCCAGTGGGCCCTGAGACAGATC GCCGACTTCGCCCTGAAGCTGCACAAGACCCATCTGGCCAGCTTTCTGAGCGCCTTCGCCAGGCAGGAAC TGTACCTGATGGGCAGCCTGGTCCACAGCATGCTGGTGCATACCACCGAGCGGCGGGAGATCTTCATCGT GGAGACAGGCCTGTGTAGCCTGGCCGAGCTGTCCCACTTTACCCAGCTGCTGGCCCACCCTCACCACGAG TACCTGAGCGACCTGTACACCCCCTGCAGCAGCAGCGGCAGACGGGACCACAGCCTGGAACGGCTGACCA GACTGTTCCCCGATGCCACCGTGCCTGCTACAGTGCCTGCCGCCCTGTCCATCCTGTCCACCATGCAGCC CAGCACCCTGGAAACCTTCCCCGACCTGTTCTGCCTGCCCCTGGGCGAGAGCTTTAGCGCCCTGACCGTG TCCGAGCACGTGTCCTACATCGTGACCAATCAGTACCTGATCAAGGGCATCAGCTACCCCGTGTCCACCA CAGTCGTGGGCCAGAGCCTGATCATCACCCAGACCGACAGCCAGACCAAGTGCGAGCTGACCCGGAACAT GCACACCACACACAGCATCACCGTGGCCCTGAACATCAGCCTGGAAAACTGCGCTTTCTGTCAGTCTGCC CTGCTGGAATACGACGATACCCAGGGCGTGATCAACATCATGTACATGCACGACAGCGACGACGTGCTGT TCGCCCTGGACCCCTACAACGAGGTGGTGGTGTCCAGCCCCCGGACCCACTACCTGATGCTGCTGAAGAA CGGCACCGTGCTGGAAGTGACCGACGTGGTGGTGGACGCCACCGACAGCAGACTGCTGATGATGAGCGTG TACGCCCTGAGCGCCATCATCGGCATCTACCTGCTGTACCGGATGCTGAAAACCTGCTGATAATCTAGAG GCCCCTATAACTCT CTACGGCTAACCTGAATGGACTACGACATAGTCTAGTCCGCCAAGATGTGCAGAAG GCCCGACTGCGGCTTCAGCTTCAGCCCTGGACCCGTGATCCTGCTGTGGTGCTGCCTGCTGCTGCCTATC GTGTCCTCTGCCGCCGTGTCTGTGGCCCCTACAGCCGCCGAGAAGGTGCCAGCCGAGTGCCCCGAGCTGA CCAGAAGATGCCTGCTGGGCGAGGTGTTCGAGGGCGACAAGTACGAGAGCTGGCTGCGGCCCCTGGTCAA CGTGACCGGCAGAGATGGCCCCCTGAGCCAGCTGATCCGGTACAGACCCGTGACCCCCGAGGCCGCCAAT AGCGTGCTGCTGGACGAGGCCTTCCTGGATACCCTGGCCCTGCTGTACAACAACCCCGACCAGCTGAGAG CCCTGCTGACCCTGCTGTCCAGCGACACCGCCCCCAGATGGATGACCGTGATGCGGGGCTACAGCGAGTG TGGAGATGGCAGCCCTGCCGTGTACACCTGCGTGGACGACCTGTGCAGAGGCTACGACCTGACCAGACTG AGCTACGGCCGGTCCATCTTCACAGAGCACGTGCTGGGCTTCGAGCTGGTGCCCCCCAGCCTGTTCAACG TGGTGGTGGCCATCCGGAACGAGGCCACCAGAACCAACAGAGCCGTGCGGCTGCCTGTGTCTACAGCCGC TGCACCTGAGGGCATCACACTGTTCTACGGCCTGTACAACGCCGTGAAAGAGTTCTGCCTCCGGCACCAG CTGGATCCCCCCCTGCTGAGACACCTGGACAAGTACTACGCCGGCCTGCCCCCAGAGCTGAAGCAGACCA GAGTGAACCTGCCCGCCCACAGCAGATATGGCCCTCAGGCCGTGGACGCCAGATGATAACGCCGGCGGCC CCTATAACTCTCTACGGCTAACCTGAATGGACTACGACATAGTCTAGTCCGCCAAGATGAGCCCCAAGGA CCTGACCCCCTTCCTGACAA CCCTGTGGCTGCTCCTGGGCCATAGCAGAGTGCCTAGAGTGCGGGCCGAG GAATGCTGCGAGTTCATCAACGTGAACCACCCCCCCGAGCGGTGCTACGACTTCAAGATGTGCAACCGGT TCACCGTGGCCCTGAGATGCCCCGACGGCGAAGTGTGCTACAGCCCCGAGAAAACCGCCGAGATCCGGGG CATCGTGACCACCATGACCCACAGCCTGACCCGGCAGGTGGTGCACAACAAGCTGACCAGCTGCAACTAC AACCCCCTGTACCTGGAAGCCGACGGCCGGATCAGATGCGGCAAAGTGAACGACAAGGCCCAGTACCTGC TGGGAGCCGCCGGAAGCGTGCCCTACCGGTGGATCAACCTGGAATACGACAAGATCACCCGGATCGTGGG CCTGGACCAGTACCTGGAAAGCGTGAAGAAGCACAAGCGGCTGGACGTGTGCAGAGCCAAGATGGGCTAC ATGCTGCAGTGATAAGGCGCGCCAACGTTACTGGCCGAAGCCGCTTGGAATAAGGCCGGTGTGCGTTTGT CTATATGTTATTTTCCACCATATTGCCGTCTTTTGGCAATGTGAGGGCCCGGAAACCTGGCCCTGTCTTC TTGACGAGCATTCCTAGGGGTCTTTCCCCTCTCGCCAAAGGAATGCAAGGTCTGTTGAATGTCGTGAAGG AAGCAGTTCCTCTGGAAGCTTCTTGAAGACAAACAACGTCTGTAGCGACCCTTTGCAGGCAGCGGAACCC CCCACCTGGCGACAGGTGCCTCTGCGGCCAAAAGCCACGTGTATAAGATACACCTGCAAAGGCGGCACAA CCCCAGTGCCACGTTGTGAGTTGGATAGTTGTGGAAAGAGTCAAATGGCTCTCCTCAAGCGTATTCAACA AGGGGCTGAAGGATGCCCAGAAGGTACCCCATTGTATGGGATCTGATCTGGGGCCTCGGTGCACATGCTT TACATGTGTTTAGTCGAGGTTAAAAA AACGTCTAGGCCCCCCGAACCACGGGGACGTGGTTTTCCTTTGA AAAACACGATAATATGCTGCGGCTGCTGCTGAGACACCACTTCCACTGCCTGCTGCTGTGTGCCGTGTGG GCCACCCCTTGTCTGGCCAGCCCTTGGAGCACCCTGACCGCCAACCAGAACCCTAGCCCCCCTTGGTCCA AGCTGACCTACAGCAAGCCCCACGACGCCGCCACCTTCTACTGCCCCTTTCTGTACCCCAGCCCTCCCAG AAGCCCCCTGCAGTTCAGCGGCTTCCAGAGAGTGTCCACCGGCCCTGAGTGCCGGAACGAGACACTGTAC CTGCTGTACAACCGGGAGGGCCAGACACTGGTGGAGCGGAGCAGCACCTGGGTGAAAAAAGTGATCTGGT ATCTGAGCGGCCGGAACCAGACCATCCTGCAGCGGATGCCCAGAACCGCCAGCAAGCCCAGCGACGGCAA CGTGCAGATCAGCGTGGAGGACGCCAAAATCTTCGGAGCCCACATGGTGCCCAAGCAGACCAAGCTGCTG AGATTCGTGGTCAACGACGGCACCAGATATCAGATGTGCGTGATGAAGCTGGAAAGCTGGGCCCACGTGT TCCGGGACTACTCCGTGAGCTTCCAGGTCCGGCTGACCTTCACCGAGGCCAACAACCAGACCTACACCTT CTGCACCCACCCCAACCTGATCGTGTGATAAGTACCTTTGTACGCCTGTTTTATACCCCCTCCCTGATTT GCAACTTAGAAGCAACGCAAACCAGATCAATAGTAGGTGTGACATACCAGTCGCATCTTGATCAAGCACT TCTGTATCCCCGGACCGAGTATCAATAGACTGTGCACACGGTTGAAGGAGAAAACGTCCGTTACCCGGCT AACTACTTCGAGAAGCCTAGTAACGCCATTGAAGTTGCAGAGTGTTTCGCTCAGCACTCCCCCCGTGTAG ATCAGGTCGATGAGTCACCGCATTCCCCACGG GCGACCGTGGCGGTGGCTGCGTTGGCGGCCTGCCTATG GGGTAACCCATAGGACGCTCTAATACGGACATGGCGTGAAGAGTCTATTGAGCTAGTTAGTAGTCCTCCG GCCCCTGAATGCGGCTAATCCTAACTGCGGAGCACATACCCTTAATCCAAAGGGCAGTGTGTCGTAACGG GCAACTCTGCAGCGGAACCGACTACTTTGGGTGTCCGTGTTTCTTTTTATTCTTGTATTGGCTGCTTATG GTGACAATTAAAGAATTGTTACCATATAGCTATTGGATTGGCCATCCAGTGTCAAACAGAGCTATTGTAT ATCTCTTTGTTGGATTCACACCTCTCACTCTTGAAACGTTACACACCCTCAATTACATTATACTGCTGAA CACGAAGCGCATATGCGGCTGTGCAGAGTGTGGCTGTCCGTGTGCCTGTGTGCCGTGGTGCTGGGCCAGT GCCAGAGAGAGACAGCCGAGAAGAACGACTACTACCGGGTGCCCCACTACTGGGATGCCTGCAGCAGAGC CCTGCCCGACCAGACCCGGTACAAATACGTGGAGCAGCTCGTGGACCTGACCCTGAACTACCACTACGAC GCCAGCCACGGCCTGGACAACTTCGACGTGCTGAAGCGGATCAACGTGACCGAGGTGTCCCTGCTGATCA GCGACTTCCGGCGGCAGAACAGAAGAGGCGGCACCAACAAGCGGACCACCTTCAACGCCGCTGGCTCTCT GGCCCCTCACGCCAGATCCCTGGAATTCAGCGTGCGGCTGTTCGCCAACTGATAACGTTGCATCCTGCAG GATACAGCAGCAATTGGCAAGCTGCTTACATAGAACTCGCGGCGATTGGCATGCCGCCTTAAAATTTTTA TTTTATTTTTCTTTTCTTTTCCGAATCGGATTTTGTTTTTAATATTTCAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAGGGTCGGCATGGCATCTCCACCTCC TCGCGGTCCGACCTGGGCATCCGAAGGAGGAC GCACGTCCACTCGGATGGCTAAGGGAGAGCCACGTTTAAACGCTAGAGCAAGACGTTTCCCGTTGAATAT GGCTCATAACACCCCTTGTATTACTGTTTATGTAAGCAGACAGTTTTATTGTTCATGATGATATATTTTT ATCTTGTGCAATGTAACATCAGAGATTTTGAGACACAACGTGGCTTTGTTGAATAAATCGAACTTTTGCT GAGTTGAAGGATCAGATCACGCATCTTCCCGACAACGCAGACCGTTCCGTGGCAAAGCAAAAGTTCAAAA TCACCAACTGGTCCACCTACAACAAAGCTCTCATCAACCGTGGCTCCCTCACTTTCTGGCTGGATGATGG GGCGATTCAGGCCTGGTATGAGTCAGCAACACCTTCTTCACGAGGCAGACCTCAGCGCTAGCGGAGTGTA TACTGGCTTACTATGTTGGCACTGATGAGGGTGTCAGTGAAGTGCTTCATGTGGCAGGAGAAAAAAGGCT GCACCGGTGCGTCAGCAGAATATGTGATACAGGATATATTCCGCTTCCTCGCTCACTGACTCGCTACGCT CGGTCGTTCGACTGCGGCGAGCGGAAATGGCTTACGAACGGGGCGGAGATTTCCTGGAAGATGCCAGGAA GATACTTAACAGGGAAGTGAGAGGGCCGCGGCAAAGCCGTTTTTCCATAGGCTCCGCCCCCCTGACAAGC ATCACGAAATCTGACGCTCAAATCAGTGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCC CCTGGCGGCTCCCTCGTGCGCTCTCCTGTTCCTGCCTTTCGGTTTACCGGTGTCATTCCGCTGTTATGGC CGCGTTTGTCTCATTCCACGCCTGACACTCAGTTCCGGGTAGGCAGTTCGCTCCAAGCTGGACTGTATGC ACGAACCCCCCGTTCAGTCCGACCGCTGCGCCTTATCCGGTAAC TATCGTCTTGAGTCCAACCCGGAAAG ACATGCAAAAGCACCACTGGCAGCAGCCACTGGTAATTGATTTAGAGGAGTTAGTCTTGAAGTCATGCGC CGGTTAAGGCTAAACTGAAAGGACAAGTTTTGGTGACTGCGCTCCTCCAAGCCAGTTACCTCGGTTCAAA GAGTTGGTAGCTCAGAGAACCTTCGAAAAACCGCCCTGCAAGGCGGTTTTTTCGTTTTCAGAGCAAGAGA TTACGCGCAGACCAAAACGATCTCAAGAAGATCATCTTATTAAGGGGTCTGACGCTCAGTGGAACGAAAA CTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAA TGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTATTAGAAAAATTCATCCA GCAGACGATAAAACGCAATACGCTGGCTATCCGGTGCCGCAATGCCATACAGCACCAGAAAACGATCCGC CCATTCGCCGCCCAGTTCTTCCGCAATATCACGGGTGGCCAGCGCAATATCCTGATAACGATCCGCCACG CCCAGACGGCCGCAATCAATAAAGCCGCTAAAACGGCCATTTTCCACCATAATGTTCGGCAGGCACGCAT CACCATGGGTCACCACCAGATCTTCGCCATCCGGCATGCTCGCTTTCAGACGCGCAAACAGCTCTGCCGG TGCCAGGCCCTGATGTTCTTCATCCAGATCATCCTGATCCACCAGGCCCGCTTCCATACGGGTACGCGCA CGTTCAATACGATGTTTCGCCTGATGATCAAACGGACAGGTCGCCGGGTCCAGGGTATGCAGACGACGCA TGGCATCCGCCATAATGCTCACTTTTTCTGCCGGCGCCAGATGGCTAGACAGCAGATCCTGACCCGGCAC TTCGCCCAGCAGCAGCCAATCACGGCCCGCTTCGGTCACCACATCCAGCA CCGCCGCACACGGAACACCG GTGGTGGCCAGCCAGCTCAGACGCGCCGCTTCATCCTGCAGCTCGTTCAGCGCACCGCTCAGATCGGTTT TCACAAACAGCACCGGACGACCCTGCGCGCTCAGACGAAACACCGCCGCATCAGAGCAGCCAATGGTCTG CTGCGCCCAATCATAGCCAAACAGACGTTCCACCCACGCTGCCGGGCTACCCGCATGCAGGCCATCCTGT TCAATCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACA TATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTAA ATTGTAAGCGTTAATATTTTGTTAAAATTCGCGTTAAATTTTTGTTAAATCAGCTCATTTTTTAACCAAT AGGCCGAAATCGGCAAAATCCCTTATAAATCAAAAGAATAGACCGAGATAGGGTTGAGTGGCCGCTACAG GGCGCTCCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGTTTCGGTGCGGGCCTCTTCGCTAT TACGCCAGCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTC ACACGCGTAATACGACTCACTATAG Vector A531: SGP-gHsol-SGP-gl ATAGGCGGCGCATGAGAGAAGCCCAGACCAATTACCTACCCAAAATGGAGAAAGTTCACGTTGACATCGA GGAAGACAGCCCATTCCTCAGAGCTTTGCAGCGGAGCTTCCCGCAGTTTGAGGTAGAAGCCAAGCAGGTC ACTGATAATGACCATGCTAATGCCAGAGCGTTTTCGCATCTGGCTTCAAAACTGATCGAAACGGAGGTGG ACCCATCCGACACGATCCTTGACATTGGAAGTGCGCCCGCCCGCAGAATGTATTCTAAGCACAAGTATCA TTGTATCTGTCCGATGAGATGTGCGGAAGATCCGGACAGATTGTATAAGTATGCAACTAAGCTGAAGAAA AACTGTAAGGAAATAACTGATAAGGAATTGGACAAGAAAATGAAGGAGCTCGCCGCCGTCATGAGCGACC CTGACCTGGAAACTGAGACTATGTGCCTCCACGACGACGAGTCGTGTCGCTACGAAGGGCAAGTCGCTGT TTACCAGGATGTATACGCGGTTGACGGACCGACAAGTCTCTATCACCAAGCCAATAAGGGAGTTAGAGTC GCCTACTGGATAGGCTTTGACACCACCCCTTTTATGTTTAAGAACTTGGCTGGAGCATATCCATCATACT CTACCAACTGGGCCGACGAAACCGTGTTAACGGCTCGTAACATAGGCCTATGCAGCTCTGACGTTATGGA GCGGTCACGTAGAGGGATGTCCATTCTTAGAAAGAAGTATTTGAAACCATCCAACAATGTTCTATTCTCT GTTGGCTCGACCATCTACCACGAGAAGAGGGACTTACTGAGGAGCTGGCACCTGCCGTCTGTATTTCACT TACGTGGCAAGCAAAATTACACATGTCGGTGTGAGACTATAGTTAGTTGCGACGGGTACGTCGTTAAAAG AATAGCTATCAGTCCAGGCCTGTATGGGAAGCCTTCAGGCTATGCTGCTACGATGCACCG CGAGGGATTC TTGTGCTGCAAAGTGACAGACACATTGAACGGGGAGAGGGTCTCTTTTCCCGTGTGCACGTATGTGCCAG CTACATTGTGTGACCAAATGACTGGCATACTGGCAACAGATGTCAGTGCGGACGACGCGCAAAAACTGCT GGTTGGGCTCAACCAGCGTATAGTCGTCAACGGTCGCACCCAGAGAAACACCAATACCATGAAAAATTAC CTTTTGCCCGTAGTGGCCCAGGCATTTGCTAGGTGGGCAAAGGAATATAAGGAAGATCAAGAAGATGAAA GGCCACTAGGACTACGAGATAGACAGTTAGTCATGGGGTGTTGTTGGGCTTTTAGAAGGCACAAGATAAC ATCTATTTATAAGCGCCCGGATACCCAAACCATCATCAAAGTGAACAGCGATTTCCACTCATTCGTGCTG CCCAGGATAGGCAGTAACACATTGGAGATCGGGCTGAGAACAAGAATCAGGAAAATGTTAGAGGAGCACA AGGAGCCGTCACCTCTCATTACCGCCGAGGACGTACAAGAAGCTAAGTGCGCAGCCGATGAGGCTAAGGA GGTGCGTGAAGCCGAGGAGTTGCGCGCAGCTCTACCACCTTTGGCAGCTGATGTTGAGGAGCCCACTCTG GAAGCCGATGTCGACTTGATGTTACAAGAGGCTGGGGCCGGCTCAGTGGAGACACCTCGTGGCTTGATAA AGGTTACCAGCTACGATGGCGAGGACAAGATCGGCTCTTACGCTGTGCTTTCTCCGCAGGCTGTACTCAA GAGTGAAAAATTATCTTGCATCCACCCTCTCGCTGAACAAGTCATAGTGATAACACACTCTGGCCGAAAA GGGCGTTATGCCGTGGAACCATACCATGGTAAAGTAGTGGTGCCAGAGGGACATGCAATACCCGTCCAGG ACTTTCAAGCTCTGAGTGAAAGTGCCACCATTGTGTACAACGAACGTGAGTTCGTAAACAGGTACC TGCA CCATATTGCCACACATGGAGGAGCGCTGAACACTGATGAAGAATATTACAAAACTGTCAAGCCCAGCGAG CACGACGGCGAATACCTGTACGACATCGACAGGAAACAGTGCGTCAAGAAAGAACTAGTCACTGGGCTAG GGCTCACAGGCGAGCTGGTGGATCCTCCCTTCCATGAATTCGCCTACGAGAGTCTGAGAACACGACCAGC CGCTCCTTACCAAGTACCAACCATAGGGGTGTATGGCGTGCCAGGATCAGGCAAGTCTGGCATCATTAAA AGCGCAGTCACCAAAAAAGATCTAGTGGTGAGCGCCAAGAAAGAAAACTGTGCAGAAATTATAAGGGACG TCAAGAAAATGAAAGGGCTGGACGTCAATGCCAGAACTGTGGACTCAGTGCTCTTGAATGGATGCAAACA CCCCGTAGAGACCCTGTATATTGACGAAGCTTTTGCTTGTCATGCAGGTACTCTCAGAGCGCTCATAGCC ATTATAAGACCTAAAAAGGCAGTGCTCTGCGGGGATCCCAAACAGTGCGGTTTTTTTAACATGATGTGCC TGAAAGTGCATTTTAACCACGAGATTTGCACACAAGTCTTCCACAAAAGCATCTCTCGCCGTTGCACTAA ATCTGTGACTTCGGTCGTCTCAACCTTGTTTTACGACAAAAAAATGAGAACGACGAATCCGAAAGAGACT AAGATTGTGATTGACACTACCGGCAGTACCAAACCTAAGCAGGACGATCTCATTCTCACTTGTTTCAGAG GGTGGGTGAAGCAGTTGCAAATAGATTACAAAGGCAACGAAATAATGACGGCAGCTGCCTCTCAAGGGCT GACCCGTAAAGGTGTGTATGCCGTTCGGTACAAGGTGAATGAAAATCCTCTGTACGCACCCACCTCAGAA CATGTGAACGTCCTACTGACCCGCACGGAGGACCGCATCGTGTGGAAAACACTAGCCGGCGACCCATGGA T AAAAACACTGACTGCCAAGTACCCTGGGAATTTCACTGCCACGATAGAGGAGTGGCAAGCAGAGCATGA TGCCATCATGAGGCACATCTTGGAGAGACCGGACCCTACCGACGTCTTCCAGAATAAGGCAAACGTGTGT TGGGCCAAGGCTTTAGTGCCGGTGCTGAAGACCGCTGGCATAGACATGACCACTGAACAATGGAACACTG TGGATTATTTTGAAACGGACAAAGCTCACTCAGCAGAGATAGTATTGAACCAACTATGCGTGAGGTTCTT TGGACTCGATCTGGACTCCGGTCTATTTTCTGCACCCACTGTTCCGTTATCCATTAGGAATAATCACTGG GATAACTCCCCGTCGCCTAACATGTACGGGCTGAATAAAGAAGTGGTCCGTCAGCTCTCTCGCAGGTACC CACAACTGCCTCGGGCAGTTGCCACTGGAAGAGTCTATGACATGAACACTGGTACACTGCGCAATTATGA TCCGCGCATAAACCTAGTACCTGTAAACAGAAGACTGCCTCATGCTTTAGTCCTCCACCATAATGAACAC CCACAGAGTGACTTTTCTTCATTCGTCAGCAAATTGAAGGGCAGAACTGTCCTGGTGGTCGGGGAAAAGT TGTCCGTCCCAGGCAAAATGGTTGACTGGTTGTCAGACCGGCCTGAGGCTACCTTCAGAGCTCGGCTGGA TTTAGGCATCCCAGGTGATGTGCCCAAATATGACATAATATTTGTTAATGTGAGGACCCCATATAAATAC CATCACTATCAGCAGTGTGAAGACCATGCCATTAAGCTTAGCATGTTGACCAAGAAAGCTTGTCTGCATC TGAATCCCGGCGGAACCTGTGTCAGCATAGGTTATGGTTACGCTGACAGGGCCAGCGAAAGCATCATTGG TGCTATAGCGCGGCAGTTCAAGTTTTCCCGGGTATGCAAACCGAAATCCTCACTTGAAGAGACGGAAGTT CTGTTTG TATTCATTGGGTACGATCGCAAGGCCCGTACGCACAATCCTTACAAGCTTTCATCAACCTTGA CCAACATTTATACAGGTTCCAGACTCCACGAAGCCGGATGTGCACCCTCATATCATGTGGTGCGAGGGGA TATTGCCACGGCCACCGAAGGAGTGATTATAAATGCTGCTAACAGCAAAGGACAACCTGGCGGAGGGGTG TGCGGAGCGCTGTATAAGAAATTCCCGGAAAGCTTCGATTTACAGCCGATCGAAGTAGGAAAAGCGCGAC TGGTCAAAGGTGCAGCTAAACATATCATTCATGCCGTAGGACCAAACTTCAACAAAGTTTCGGAGGTTGA AGGTGACAAACAGTTGGCAGAGGCTTATGAGTCCATCGCTAAGATTGTCAACGATAACAATTACAAGTCA GTAGCGATTCCACTGTTGTCCACCGGCATCTTTTCCGGGAACAAAGATCGACTAACCCAATCATTGAACC ATTTGCTGACAGCTTTAGACACCACTGATGCAGATGTAGCCATATACTGCAGGGACAAGAAATGGGAAAT GACTCTCAAGGAAGCAGTGGCTAGGAGAGAAGCAGTGGAGGAGATATGCATATCCGACGACTCTTCAGTG ACAGAACCTGATGCAGAGCTGGTGAGGGTGCATCCGAAGAGTTCTTTGGCTGGAAGGAAGGGCTACAGCA CAAGCGATGGCAAAACTTTCTCATATTTGGAAGGGACCAAGTTTCACCAGGCGGCCAAGGATATAGCAGA AATTAATGCCATGTGGCCCGTTGCAACGGAGGCCAATGAGCAGGTATGCATGTATATCCTCGGAGAAAGC ATGAGCAGTATTAGGTCGAAATGCCCCGTCGAAGAGTCGGAAGCCTCCACACCACCTAGCACGCTGCCTT GCTTGTGCATCCATGCCATGACTCCAGAAAGAGTACAGCGCCTAAAAGCCTCACGTCCAGAACAAATTAC TGTGTGCTCATCC TTTCCATTGCCGAAGTATAGAATCACTGGTGTGCAGAAGATCCAATGCTCCCAGCCT ATATTGTTCTCACCGAAAGTGCCTGCGTATATTCATCCAAGGAAGTATCTCGTGGAAACACCACCGGTAG ACGAGACTCCGGAGCCATCGGCAGAGAACCAATCCACAGAGGGGACACCTGAACAACCACCACTTATAAC CGAGGATGAGACCAGGACTAGAACGCCTGAGCCGATCATCATCGAAGAGGAAGAAGAGGATAGCATAAGT TTGCTGTCAGATGGCCCGACCCACCAGGTGCTGCAAGTCGAGGCAGACATTCACGGGCCGCCCTCTGTAT CTAGCTCATCCTGGTCCATTCCTCATGCATCCGACTTTGATGTGGACAGTTTATCCATACTTGACACCCT GGAGGGAGCTAGCGTGACCAGCGGGGCAACGTCAGCCGAGACTAACTCTTACTTCGCAAAGAGTATGGAG TTTCTGGCGCGACCGGTGCCTGCGCCTCGAACAGTATTCAGGAACCCTCCACATCCCGCTCCGCGCACAA GAACACCGTCACTTGCACCCAGCAGGGCCTGCTCGAGAACCAGCCTAGTTTCCACCCCGCCAGGCGTGAA TAGGGTGATCACTAGAGAGGAGCTCGAGGCGCTTACCCCGTCACGCACTCCTAGCAGGTCGGTCTCGAGA ACCAGCCTGGTCTCCAACCCGCCAGGCGTAAATAGGGTGATTACAAGAGAGGAGTTTGAGGCGTTCGTAG CACAACAACAATGACGGTTTGATGCGGGTGCATACATCTTTTCCTCCGACACCGGTCAAGGGCATTTACA ACAAAAATCAGTAAGGCAAACGGTGCTATCCGAAGTGGTGTTGGAGAGGACCGAATTGGAGATTTCGTAT GCCCCGCGCCTCGACCAAGAAAAAGAAGAATTACTACGCAAGAAATTACAGTTAAATCCCACACCTGCTA ACAGAAGCAGATACCAGTC CAGGAAGGTGGAGAACATGAAAGCCATAACAGCTAGACGTATTCTGCAAGG CCTAGGGCATTATTTGAAGGCAGAAGGAAAAGTGGAGTGCTACCGAACCCTGCATCCTGTTCCTTTGTAT TCATCTAGTGTGAACCGTGCCTTTTCAAGCCCCAAGGTCGCAGTGGAAGCCTGTAACGCCATGTTGAAAG AGAACTTTCCGACTGTGGCTTCTTACTGTATTATTCCAGAGTACGATGCCTATTTGGACATGGTTGACGG AGCTTCATGCTGCTTAGACACTGCCAGTTTTTGCCCTGCAAAGCTGCGCAGCTTTCCAAAGAAACACTCC TATTTGGAACCCACAATACGATCGGCAGTGCCTTCAGCGATCCAGAACACGCTCCAGAACGTCCTGGCAG CTGCCACAAAAAGAAATTGCAATGTCACGCAAATGAGAGAATTGCCCGTATTGGATTCGGCGGCCTTTAA TGTGGAATGCTTCAAGAAATATGCGTGTAATAATGAATATTGGGAAACGTTTAAAGAAAACCCCATCAGG CTTACTGAAGAAAACGTGGTAAATTACATTACCAAATTAAAAGGACCAAAAGCTGCTGCTCTTTTTGCGA AGACACATAATTTGAATATGTTGCAGGACATACCAATGGACAGGTTTGTAATGGACTTAAAGAGAGACGT GAAAGTGACTCCAGGAACAAAACATACTGAAGAACGGCCCAAGGTACAGGTGATCCAGGCTGCCGATCCG CTAGCAACAGCGTATCTGTGCGGAATCCACCGAGAGCTGGTTAGGAGATTAAATGCGGTCCTGCTTCCGA ACATTCATACACTGTTTGATATGTCGGCTGAAGACTTTGACGCTATTATAGCCGAGCACTTCCAGCCTGG GGATTGTGTTCTGGAAACTGACATCGCGTCGTTTGATAAAAGTGAGGACGACGCCATGGCTCTGACCGCG TTAATGATTCTGGAAGACTTAGGTG TGGACGCAGAGCTGTTGACGCTGATTGAGGCGGCTTTCGGCGAAA TTTCATCAATACATTTGCCCACTAAAACTAAATTTAAATTCGGAGCCATGATGAAATCTGGAATGTTCCT CACACTGTTTGTGAACACAGTCATTAACATTGTAATCGCAAGCAGAGTGTTGAGAGAACGGCTAACCGGA TCACCATGTGCAGCATTCATTGGAGATGACAATATCGTGAAAGGAGTCAAATCGGACAAATTAATGGCAG ACAGGTGCGCCACCTGGTTGAATATGGAAGTCAAGATTATAGATGCTGTGGTGGGCGAGAAAGCGCCTTA TTTCTGTGGAGGGTTTATTTTGTGTGACTCCGTGACCGGCACAGCGTGCCGTGTGGCAGACCCCCTAAAA AGGCTGTTTAAGCTTGGCAAACCTCTGGCAGCAGACGATGAACATGATGATGACAGGAGAAGGGCATTGC ATGAAGAGTCAACACGCTGGAACCGAGTGGGTATTCTTTCAGAGCTGTGCAAGGCAGTAGAATCAAGGTA TGAAACCGTAGGAACTTCCATCATAGTTATGGCCATGACTACTCTAGCTAGCAGTGTTAAATCATTCAGC TACCTGAGAGGGGCCCCTATAACTCTCTACGGCTAACCTGAATGGACTACGACATAGTCTAGTCCGCCAA GATGAGGCCTGGCCTGCCCTCCTACCTGATCATCCTGGCCGTGTGCCTGTTCAGCCACCTGCTGTCCAGC AGATACGGCGCCGAGGCCGTGAGCGAGCCCCTGGACAAGGCTTTCCACCTGCTGCTGAACACCTACGGCA GACCCATCCGGTTTCTGCGGGAGAACACCACCCAGTGCACCTACAACAGCAGCCTGCGGAACAGCACCGT CGTGAGAGAGAACGCCATCAGCTTCAACTTTTTCCAGAGCTACAACCAGTACTACGTGTTCCACATGCCC AGATGCCTGTTTGCCGGCCCTCTGGCCGAGC AGTTCCTGAACCAGGTGGACCTGACCGAGACACTGGAAA GATACCAGCAGCGGCTGAATACCTACGCCCTGGTGTCCAAGGACCTGGCCAGCTACCGGTCCTTTAGCCA GCAGCTCAAGGCTCAGGATAGCCTCGGCGAGCAGCCTACCACCGTGCCCCCTCCCATCGACCTGAGCATC CCCCACGTGTGGATGCCTCCCCAGACCACCCCTCACGGCTGGACCGAGAGCCACACCACCTCCGGCCTGC ACAGACCCCACTTCAACCAGACCTGCATCCTGTTCGACGGCCACGACCTGCTGTTTAGCACCGTGACCCC CTGCCTGCACCAGGGCTTCTACCTGATCGACGAGCTGAGATACGTGAAGATCACCCTGACCGAGGATTTC TTCGTGGTCACCGTGTCCATCGACGACGACACCCCCATGCTGCTGATCTTCGGCCACCTGCCCAGAGTGC TGTTCAAGGCCCCCTACCAGCGGGACAACTTCATCCTGCGGCAGACCGAGAAGCACGAGCTGCTGGTGCT GGTCAAGAAGGACCAGCTGAACCGGCACTCCTACCTGAAGGACCCCGACTTCCTGGACGCCGCCCTGGAC TTCAACTACCTGGACCTGAGCGCCCTGCTGAGAAACAGCTTCCACAGATACGCCGTGGACGTGCTGAAGT CCGGACGGTGCCAGATGCTCGATCGGCGGACCGTGGAGATGGCCTTCGCCTATGCCCTCGCCCTGTTCGC CGCTGCCAGACAGGAAGAGGCTGGCGCCCAGGTGTCAGTGCCCAGAGCCCTGGATAGACAGGCCGCCCTG CTGCAGATCCAGGAATTCATGATCACCTGCCTGAGCCAGACCCCCCCTAGAACCACCCTGCTGCTGTACC CCACAGCCGTGGATCTGGCCAAGAGGGCCCTGTGGACCCCCAACCAGATCACCGACATCACAAGCCTCGT GCGGCTCGTGTACATCCTGAGCAAGCAGAACCAGCAG CACCTGATCCCCCAGTGGGCCCTGAGACAGATC GCCGACTTCGCCCTGAAGCTGCACAAGACCCATCTGGCCAGCTTTCTGAGCGCCTTCGCCAGGCAGGAAC TGTACCTGATGGGCAGCCTGGTCCACAGCATGCTGGTGCATACCACCGAGCGGCGGGAGATCTTCATCGT GGAGACAGGCCTGTGTAGCCTGGCCGAGCTGTCCCACTTTACCCAGCTGCTGGCCCACCCTCACCACGAG TACCTGAGCGACCTGTACACCCCCTGCAGCAGCAGCGGCAGACGGGACCACAGCCTGGAACGGCTGACCA GACTGTTCCCCGATGCCACCGTGCCTGCTACAGTGCCTGCCGCCCTGTCCATCCTGTCCACCATGCAGCC CAGCACCCTGGAAACCTTCCCCGACCTGTTCTGCCTGCCCCTGGGCGAGAGCTTTAGCGCCCTGACCGTG TCCGAGCACGTGTCCTACATCGTGACCAATCAGTACCTGATCAAGGGCATCAGCTACCCCGTGTCCACCA CAGTCGTGGGCCAGAGCCTGATCATCACCCAGACCGACAGCCAGACCAAGTGCGAGCTGACCCGGAACAT GCACACCACACACAGCATCACCGTGGCCCTGAACATCAGCCTGGAAAACTGCGCTTTCTGTCAGTCTGCC CTGCTGGAATACGACGATACCCAGGGCGTGATCAACATCATGTACATGCACGACAGCGACGACGTGCTGT TCGCCCTGGACCCCTACAACGAGGTGGTGGTGTCCAGCCCCCGGACCCACTACCTGATGCTGCTGAAGAA CGGCACCGTGCTGGAAGTGACCGACGTGGTGGTGGACGCCACCGACTGATAATCTAGAGGCCCCTATAAC TCTCTACGGCTAACCTGAATGGACTACGACATAGTCTAGTCCGCCAAGATGTGCAGAAGGCCCGACTGCG GCTTCAGCTTCAGCCCTGGACCCGTGATCCTGCTGTGGTGCTG CCTGCTGCTGCCTATCGTGTCCTCTGC CGCCGTGTCTGTGGCCCCTACAGCCGCCGAGAAGGTGCCAGCCGAGTGCCCCGAGCTGACCAGAAGATGC CTGCTGGGCGAGGTGTTCGAGGGCGACAAGTACGAGAGCTGGCTGCGGCCCCTGGTCAACGTGACCGGCA GAGATGGCCCCCTGAGCCAGCTGATCCGGTACAGACCCGTGACCCCCGAGGCCGCCAATAGCGTGCTGCT GGACGAGGCCTTCCTGGATACCCTGGCCCTGCTGTACAACAACCCCGACCAGCTGAGAGCCCTGCTGACC CTGCTGTCCAGCGACACCGCCCCCAGATGGATGACCGTGATGCGGGGCTACAGCGAGTGTGGAGATGGCA GCCCTGCCGTGTACACCTGCGTGGACGACCTGTGCAGAGGCTACGACCTGACCAGACTGAGCTACGGCCG GTCCATCTTCACAGAGCACGTGCTGGGCTTCGAGCTGGTGCCCCCCAGCCTGTTCAACGTGGTGGTGGCC ATCCGGAACGAGGCCACCAGAACCAACAGAGCCGTGCGGCTGCCTGTGTCTACAGCCGCTGCACCTGAGG GCATCACACTGTTCTACGGCCTGTACAACGCCGTGAAAGAGTTCTGCCTCCGGCACCAGCTGGATCCCCC CCTGCTGAGACACCTGGACAAGTACTACGCCGGCCTGCCCCCAGAGCTGAAGCAGACCAGAGTGAACCTG CCCGCCCACAGCAGATATGGCCCTCAGGCCGTGGACGCCAGATGATAAGCGGCCGCATACAGCAGCAATT GGCAAGCTGCTTACATAGAACTCGCGGCGATTGGCATGCCGCCTTAAAATTTTTATTTTATTTTTCTTTT CTTTTCCGAATCGGATTTTGTTTTTAATATTTCAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAGG GTCGGCATGGCATCTCCACCTCCTCGCGGTCCGACCTGGGCATCCGAAG GAGGACGCACGTCCACTCGGA TGGCTAAGGGAGAGCCACGTTTAAACACGTGATATCTGGCCTCATGGGCCTTCCTTTCACTGCCCGCTTT CCAGTCGGGAAACCTGTCGTGCCAGCTGCATTAACATGGTCATAGCTGTTTCCTTGCGTATTGGGCGCTC TCCGCTTCCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGGTAAAGCCTGGGGTGCCTAATGAGCAAA AGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCT GACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGG CGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGC CTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTC GTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACT ATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAG CAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGA ACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCG GCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGG ATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGG ATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAA AATGAAGTTTTAAAT CAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTATTAGAAAAATTCATCCAGCAGACGATAAAA CGCAATACGCTGGCTATCCGGTGCCGCAATGCCATACAGCACCAGAAAACGATCCGCCCATTCGCCGCCC AGTTCTTCCGCAATATCACGGGTGGCCAGCGCAATATCCTGATAACGATCCGCCACGCCCAGACGGCCGC AATCAATAAAGCCGCTAAAACGGCCATTTTCCACCATAATGTTCGGCAGGCACGCATCACCATGGGTCAC CACCAGATCTTCGCCATCCGGCATGCTCGCTTTCAGACGCGCAAACAGCTCTGCCGGTGCCAGGCCCTGA TGTTCTTCATCCAGATCATCCTGATCCACCAGGCCCGCTTCCATACGGGTACGCGCACGTTCAATACGAT GTTTCGCCTGATGATCAAACGGACAGGTCGCCGGGTCCAGGGTATGCAGACGACGCATGGCATCCGCCAT AATGCTCACTTTTTCTGCCGGCGCCAGATGGCTAGACAGCAGATCCTGACCCGGCACTTCGCCCAGCAGC AGCCAATCACGGCCCGCTTCGGTCACCACATCCAGCACCGCCGCACACGGAACACCGGTGGTGGCCAGCC AGCTCAGACGCGCCGCTTCATCCTGCAGCTCGTTCAGCGCACCGCTCAGATCGGTTTTCACAAACAGCAC CGGACGACCCTGCGCGCTCAGACGAAACACCGCCGCATCAGAGCAGCCAATGGTCTGCTGCGCCCAATCA TAGCCAAACAGACGTTCCACCCACGCTGCCGGGCTACCCGCATGCAGGCCATCCTGTTCAATCATACTCT TCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTAT TTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTAAATTG TAAGCGTTA ATATTTTGTTAAAATTCGCGTTAAATTTTTGTTAAATCAGCTCATTTTTTAACCAATAGGCCGAAATCGG CAAAATCCCTTATAAATCAAAAGAATAGACCGAGATAGGGTTGAGTGGCCGCTACAGGGCGCTCCCATTC GCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGTTTCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGGC GAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACACGCGTAATAC GACTCACTATAG Vector A532: SGP-gHsol-2A-gl ATAGGCGGCGCATGAGAGAAGCCCAGACCAATTACCTACCCAAAATGGAGAAAGTTCACGTTGACATCGA GGAAGACAGCCCATTCCTCAGAGCTTTGCAGCGGAGCTTCCCGCAGTTTGAGGTAGAAGCCAAGCAGGTC ACTGATAATGACCATGCTAATGCCAGAGCGTTTTCGCATCTGGCTTCAAAACTGATCGAAACGGAGGTGG ACCCATCCGACACGATCCTTGACATTGGAAGTGCGCCCGCCCGCAGAATGTATTCTAAGCACAAGTATCA TTGTATCTGTCCGATGAGATGTGCGGAAGATCCGGACAGATTGTATAAGTATGCAACTAAGCTGAAGAAA AACTGTAAGGAAATAACTGATAAGGAATTGGACAAGAAAATGAAGGAGCTCGCCGCCGTCATGAGCGACC CTGACCTGGAAACTGAGACTATGTGCCTCCACGACGACGAGTCGTGTCGCTACGAAGGGCAAGTCGCTGT TTACCAGGATGTATACGCGGTTGACGGACCGACAAGTCTCTATCACCAAGCCAATAAGGGAGTTAGAGTC GCCTACTGGATAGGCTTTGACACCACCCCTTTTATGTTTAAGAACTTGGCTGGAGCATATCCATCATACT CTACCAACTGGGCCGACGAAACCGTGTTAACGGCTCGTAACATAGGCCTATGCAGCTCTGACGTTATGGA GCGGTCACGTAGAGGGATGTCCATTCTTAGAAAGAAGTATTTGAAACCATCCAACAATGTTCTATTCTCT GTTGGCTCGACCATCTACCACGAGAAGAGGGACTTACTGAGGAGCTGGCACCTGCCGTCTGTATTTCACT TACGTGGCAAGCAAAATTACACATGTCGGTGTGAGACTATAGTTAGTTGCGACGGGTACGTCGTTAAAAG AATAGCTATCAGTCCAGGCCTGTATGGGAAGCCTTCAGGCTATGCTGCTACGATGCACCGC GAGGGATTC TTGTGCTGCAAAGTGACAGACACATTGAACGGGGAGAGGGTCTCTTTTCCCGTGTGCACGTATGTGCCAG CTACATTGTGTGACCAAATGACTGGCATACTGGCAACAGATGTCAGTGCGGACGACGCGCAAAAACTGCT GGTTGGGCTCAACCAGCGTATAGTCGTCAACGGTCGCACCCAGAGAAACACCAATACCATGAAAAATTAC CTTTTGCCCGTAGTGGCCCAGGCATTTGCTAGGTGGGCAAAGGAATATAAGGAAGATCAAGAAGATGAAA GGCCACTAGGACTACGAGATAGACAGTTAGTCATGGGGTGTTGTTGGGCTTTTAGAAGGCACAAGATAAC ATCTATTTATAAGCGCCCGGATACCCAAACCATCATCAAAGTGAACAGCGATTTCCACTCATTCGTGCTG CCCAGGATAGGCAGTAACACATTGGAGATCGGGCTGAGAACAAGAATCAGGAAAATGTTAGAGGAGCACA AGGAGCCGTCACCTCTCATTACCGCCGAGGACGTACAAGAAGCTAAGTGCGCAGCCGATGAGGCTAAGGA GGTGCGTGAAGCCGAGGAGTTGCGCGCAGCTCTACCACCTTTGGCAGCTGATGTTGAGGAGCCCACTCTG GAAGCCGATGTCGACTTGATGTTACAAGAGGCTGGGGCCGGCTCAGTGGAGACACCTCGTGGCTTGATAA AGGTTACCAGCTACGATGGCGAGGACAAGATCGGCTCTTACGCTGTGCTTTCTCCGCAGGCTGTACTCAA GAGTGAAAAATTATCTTGCATCCACCCTCTCGCTGAACAAGTCATAGTGATAACACACTCTGGCCGAAAA GGGCGTTATGCCGTGGAACCATACCATGGTAAAGTAGTGGTGCCAGAGGGACATGCAATACCCGTCCAGG ACTTTCAAGCTCTGAGTGAAAGTGCCACCATTGTGTACAACGAACGTGAGTTCGTAAACAGGTACCT GCA CCATATTGCCACACATGGAGGAGCGCTGAACACTGATGAAGAATATTACAAAACTGTCAAGCCCAGCGAG CACGACGGCGAATACCTGTACGACATCGACAGGAAACAGTGCGTCAAGAAAGAACTAGTCACTGGGCTAG GGCTCACAGGCGAGCTGGTGGATCCTCCCTTCCATGAATTCGCCTACGAGAGTCTGAGAACACGACCAGC CGCTCCTTACCAAGTACCAACCATAGGGGTGTATGGCGTGCCAGGATCAGGCAAGTCTGGCATCATTAAA AGCGCAGTCACCAAAAAAGATCTAGTGGTGAGCGCCAAGAAAGAAAACTGTGCAGAAATTATAAGGGACG TCAAGAAAATGAAAGGGCTGGACGTCAATGCCAGAACTGTGGACTCAGTGCTCTTGAATGGATGCAAACA CCCCGTAGAGACCCTGTATATTGACGAAGCTTTTGCTTGTCATGCAGGTACTCTCAGAGCGCTCATAGCC ATTATAAGACCTAAAAAGGCAGTGCTCTGCGGGGATCCCAAACAGTGCGGTTTTTTTAACATGATGTGCC TGAAAGTGCATTTTAACCACGAGATTTGCACACAAGTCTTCCACAAAAGCATCTCTCGCCGTTGCACTAA ATCTGTGACTTCGGTCGTCTCAACCTTGTTTTACGACAAAAAAATGAGAACGACGAATCCGAAAGAGACT AAGATTGTGATTGACACTACCGGCAGTACCAAACCTAAGCAGGACGATCTCATTCTCACTTGTTTCAGAG GGTGGGTGAAGCAGTTGCAAATAGATTACAAAGGCAACGAAATAATGACGGCAGCTGCCTCTCAAGGGCT GACCCGTAAAGGTGTGTATGCCGTTCGGTACAAGGTGAATGAAAATCCTCTGTACGCACCCACCTCAGAA CATGTGAACGTCCTACTGACCCGCACGGAGGACCGCATCGTGTGGAAAACACTAGCCGGCGACCCATGGA TA AAAACACTGACTGCCAAGTACCCTGGGAATTTCACTGCCACGATAGAGGAGTGGCAAGCAGAGCATGA TGCCATCATGAGGCACATCTTGGAGAGACCGGACCCTACCGACGTCTTCCAGAATAAGGCAAACGTGTGT TGGGCCAAGGCTTTAGTGCCGGTGCTGAAGACCGCTGGCATAGACATGACCACTGAACAATGGAACACTG TGGATTATTTTGAAACGGACAAAGCTCACTCAGCAGAGATAGTATTGAACCAACTATGCGTGAGGTTCTT TGGACTCGATCTGGACTCCGGTCTATTTTCTGCACCCACTGTTCCGTTATCCATTAGGAATAATCACTGG GATAACTCCCCGTCGCCTAACATGTACGGGCTGAATAAAGAAGTGGTCCGTCAGCTCTCTCGCAGGTACC CACAACTGCCTCGGGCAGTTGCCACTGGAAGAGTCTATGACATGAACACTGGTACACTGCGCAATTATGA TCCGCGCATAAACCTAGTACCTGTAAACAGAAGACTGCCTCATGCTTTAGTCCTCCACCATAATGAACAC CCACAGAGTGACTTTTCTTCATTCGTCAGCAAATTGAAGGGCAGAACTGTCCTGGTGGTCGGGGAAAAGT TGTCCGTCCCAGGCAAAATGGTTGACTGGTTGTCAGACCGGCCTGAGGCTACCTTCAGAGCTCGGCTGGA TTTAGGCATCCCAGGTGATGTGCCCAAATATGACATAATATTTGTTAATGTGAGGACCCCATATAAATAC CATCACTATCAGCAGTGTGAAGACCATGCCATTAAGCTTAGCATGTTGACCAAGAAAGCTTGTCTGCATC TGAATCCCGGCGGAACCTGTGTCAGCATAGGTTATGGTTACGCTGACAGGGCCAGCGAAAGCATCATTGG TGCTATAGCGCGGCAGTTCAAGTTTTCCCGGGTATGCAAACCGAAATCCTCACTTGAAGAGACGGAAGTT CTGTTTGT ATTCATTGGGTACGATCGCAAGGCCCGTACGCACAATCCTTACAAGCTTTCATCAACCTTGA CCAACATTTATACAGGTTCCAGACTCCACGAAGCCGGATGTGCACCCTCATATCATGTGGTGCGAGGGGA TATTGCCACGGCCACCGAAGGAGTGATTATAAATGCTGCTAACAGCAAAGGACAACCTGGCGGAGGGGTG TGCGGAGCGCTGTATAAGAAATTCCCGGAAAGCTTCGATTTACAGCCGATCGAAGTAGGAAAAGCGCGAC TGGTCAAAGGTGCAGCTAAACATATCATTCATGCCGTAGGACCAAACTTCAACAAAGTTTCGGAGGTTGA AGGTGACAAACAGTTGGCAGAGGCTTATGAGTCCATCGCTAAGATTGTCAACGATAACAATTACAAGTCA GTAGCGATTCCACTGTTGTCCACCGGCATCTTTTCCGGGAACAAAGATCGACTAACCCAATCATTGAACC ATTTGCTGACAGCTTTAGACACCACTGATGCAGATGTAGCCATATACTGCAGGGACAAGAAATGGGAAAT GACTCTCAAGGAAGCAGTGGCTAGGAGAGAAGCAGTGGAGGAGATATGCATATCCGACGACTCTTCAGTG ACAGAACCTGATGCAGAGCTGGTGAGGGTGCATCCGAAGAGTTCTTTGGCTGGAAGGAAGGGCTACAGCA CAAGCGATGGCAAAACTTTCTCATATTTGGAAGGGACCAAGTTTCACCAGGCGGCCAAGGATATAGCAGA AATTAATGCCATGTGGCCCGTTGCAACGGAGGCCAATGAGCAGGTATGCATGTATATCCTCGGAGAAAGC ATGAGCAGTATTAGGTCGAAATGCCCCGTCGAAGAGTCGGAAGCCTCCACACCACCTAGCACGCTGCCTT GCTTGTGCATCCATGCCATGACTCCAGAAAGAGTACAGCGCCTAAAAGCCTCACGTCCAGAACAAATTAC TGTGTGCTCATCCT TTCCATTGCCGAAGTATAGAATCACTGGTGTGCAGAAGATCCAATGCTCCCAGCCT ATATTGTTCTCACCGAAAGTGCCTGCGTATATTCATCCAAGGAAGTATCTCGTGGAAACACCACCGGTAG ACGAGACTCCGGAGCCATCGGCAGAGAACCAATCCACAGAGGGGACACCTGAACAACCACCACTTATAAC CGAGGATGAGACCAGGACTAGAACGCCTGAGCCGATCATCATCGAAGAGGAAGAAGAGGATAGCATAAGT TTGCTGTCAGATGGCCCGACCCACCAGGTGCTGCAAGTCGAGGCAGACATTCACGGGCCGCCCTCTGTAT CTAGCTCATCCTGGTCCATTCCTCATGCATCCGACTTTGATGTGGACAGTTTATCCATACTTGACACCCT GGAGGGAGCTAGCGTGACCAGCGGGGCAACGTCAGCCGAGACTAACTCTTACTTCGCAAAGAGTATGGAG TTTCTGGCGCGACCGGTGCCTGCGCCTCGAACAGTATTCAGGAACCCTCCACATCCCGCTCCGCGCACAA GAACACCGTCACTTGCACCCAGCAGGGCCTGCTCGAGAACCAGCCTAGTTTCCACCCCGCCAGGCGTGAA TAGGGTGATCACTAGAGAGGAGCTCGAGGCGCTTACCCCGTCACGCACTCCTAGCAGGTCGGTCTCGAGA ACCAGCCTGGTCTCCAACCCGCCAGGCGTAAATAGGGTGATTACAAGAGAGGAGTTTGAGGCGTTCGTAG CACAACAACAATGACGGTTTGATGCGGGTGCATACATCTTTTCCTCCGACACCGGTCAAGGGCATTTACA ACAAAAATCAGTAAGGCAAACGGTGCTATCCGAAGTGGTGTTGGAGAGGACCGAATTGGAGATTTCGTAT GCCCCGCGCCTCGACCAAGAAAAAGAAGAATTACTACGCAAGAAATTACAGTTAAATCCCACACCTGCTA ACAGAAGCAGATACCAGTCC AGGAAGGTGGAGAACATGAAAGCCATAACAGCTAGACGTATTCTGCAAGG CCTAGGGCATTATTTGAAGGCAGAAGGAAAAGTGGAGTGCTACCGAACCCTGCATCCTGTTCCTTTGTAT TCATCTAGTGTGAACCGTGCCTTTTCAAGCCCCAAGGTCGCAGTGGAAGCCTGTAACGCCATGTTGAAAG AGAACTTTCCGACTGTGGCTTCTTACTGTATTATTCCAGAGTACGATGCCTATTTGGACATGGTTGACGG AGCTTCATGCTGCTTAGACACTGCCAGTTTTTGCCCTGCAAAGCTGCGCAGCTTTCCAAAGAAACACTCC TATTTGGAACCCACAATACGATCGGCAGTGCCTTCAGCGATCCAGAACACGCTCCAGAACGTCCTGGCAG CTGCCACAAAAAGAAATTGCAATGTCACGCAAATGAGAGAATTGCCCGTATTGGATTCGGCGGCCTTTAA TGTGGAATGCTTCAAGAAATATGCGTGTAATAATGAATATTGGGAAACGTTTAAAGAAAACCCCATCAGG CTTACTGAAGAAAACGTGGTAAATTACATTACCAAATTAAAAGGACCAAAAGCTGCTGCTCTTTTTGCGA AGACACATAATTTGAATATGTTGCAGGACATACCAATGGACAGGTTTGTAATGGACTTAAAGAGAGACGT GAAAGTGACTCCAGGAACAAAACATACTGAAGAACGGCCCAAGGTACAGGTGATCCAGGCTGCCGATCCG CTAGCAACAGCGTATCTGTGCGGAATCCACCGAGAGCTGGTTAGGAGATTAAATGCGGTCCTGCTTCCGA ACATTCATACACTGTTTGATATGTCGGCTGAAGACTTTGACGCTATTATAGCCGAGCACTTCCAGCCTGG GGATTGTGTTCTGGAAACTGACATCGCGTCGTTTGATAAAAGTGAGGACGACGCCATGGCTCTGACCGCG TTAATGATTCTGGAAGACTTAGGTGT GGACGCAGAGCTGTTGACGCTGATTGAGGCGGCTTTCGGCGAAA TTTCATCAATACATTTGCCCACTAAAACTAAATTTAAATTCGGAGCCATGATGAAATCTGGAATGTTCCT CACACTGTTTGTGAACACAGTCATTAACATTGTAATCGCAAGCAGAGTGTTGAGAGAACGGCTAACCGGA TCACCATGTGCAGCATTCATTGGAGATGACAATATCGTGAAAGGAGTCAAATCGGACAAATTAATGGCAG ACAGGTGCGCCACCTGGTTGAATATGGAAGTCAAGATTATAGATGCTGTGGTGGGCGAGAAAGCGCCTTA TTTCTGTGGAGGGTTTATTTTGTGTGACTCCGTGACCGGCACAGCGTGCCGTGTGGCAGACCCCCTAAAA AGGCTGTTTAAGCTTGGCAAACCTCTGGCAGCAGACGATGAACATGATGATGACAGGAGAAGGGCATTGC ATGAAGAGTCAACACGCTGGAACCGAGTGGGTATTCTTTCAGAGCTGTGCAAGGCAGTAGAATCAAGGTA TGAAACCGTAGGAACTTCCATCATAGTTATGGCCATGACTACTCTAGCTAGCAGTGTTAAATCATTCAGC TACCTGAGAGGGGCCCCTATAACTCTCTACGGCTAACCTGAATGGACTACGACATAGTCTAGTCCGCCAA GATGAGGCCTGGCCTGCCCTCCTACCTGATCATCCTGGCCGTGTGCCTGTTCAGCCACCTGCTGTCCAGC AGATACGGCGCCGAGGCCGTGAGCGAGCCCCTGGACAAGGCTTTCCACCTGCTGCTGAACACCTACGGCA GACCCATCCGGTTTCTGCGGGAGAACACCACCCAGTGCACCTACAACAGCAGCCTGCGGAACAGCACCGT CGTGAGAGAGAACGCCATCAGCTTCAACTTTTTCCAGAGCTACAACCAGTACTACGTGTTCCACATGCCC AGATGCCTGTTTGCCGGCCCTCTGGCCGAGCA GTTCCTGAACCAGGTGGACCTGACCGAGACACTGGAAA GATACCAGCAGCGGCTGAATACCTACGCCCTGGTGTCCAAGGACCTGGCCAGCTACCGGTCCTTTAGCCA GCAGCTCAAGGCTCAGGATAGCCTCGGCGAGCAGCCTACCACCGTGCCCCCTCCCATCGACCTGAGCATC CCCCACGTGTGGATGCCTCCCCAGACCACCCCTCACGGCTGGACCGAGAGCCACACCACCTCCGGCCTGC ACAGACCCCACTTCAACCAGACCTGCATCCTGTTCGACGGCCACGACCTGCTGTTTAGCACCGTGACCCC CTGCCTGCACCAGGGCTTCTACCTGATCGACGAGCTGAGATACGTGAAGATCACCCTGACCGAGGATTTC TTCGTGGTCACCGTGTCCATCGACGACGACACCCCCATGCTGCTGATCTTCGGCCACCTGCCCAGAGTGC TGTTCAAGGCCCCCTACCAGCGGGACAACTTCATCCTGCGGCAGACCGAGAAGCACGAGCTGCTGGTGCT GGTCAAGAAGGACCAGCTGAACCGGCACTCCTACCTGAAGGACCCCGACTTCCTGGACGCCGCCCTGGAC TTCAACTACCTGGACCTGAGCGCCCTGCTGAGAAACAGCTTCCACAGATACGCCGTGGACGTGCTGAAGT CCGGACGGTGCCAGATGCTCGATCGGCGGACCGTGGAGATGGCCTTCGCCTATGCCCTCGCCCTGTTCGC CGCTGCCAGACAGGAAGAGGCTGGCGCCCAGGTGTCAGTGCCCAGAGCCCTGGATAGACAGGCCGCCCTG CTGCAGATCCAGGAATTCATGATCACCTGCCTGAGCCAGACCCCCCCTAGAACCACCCTGCTGCTGTACC CCACAGCCGTGGATCTGGCCAAGAGGGCCCTGTGGACCCCCAACCAGATCACCGACATCACAAGCCTCGT GCGGCTCGTGTACATCCTGAGCAAGCAGAACCAGCAGC ACCTGATCCCCCAGTGGGCCCTGAGACAGATC GCCGACTTCGCCCTGAAGCTGCACAAGACCCATCTGGCCAGCTTTCTGAGCGCCTTCGCCAGGCAGGAAC TGTACCTGATGGGCAGCCTGGTCCACAGCATGCTGGTGCATACCACCGAGCGGCGGGAGATCTTCATCGT GGAGACAGGCCTGTGTAGCCTGGCCGAGCTGTCCCACTTTACCCAGCTGCTGGCCCACCCTCACCACGAG TACCTGAGCGACCTGTACACCCCCTGCAGCAGCAGCGGCAGACGGGACCACAGCCTGGAACGGCTGACCA GACTGTTCCCCGATGCCACCGTGCCTGCTACAGTGCCTGCCGCCCTGTCCATCCTGTCCACCATGCAGCC CAGCACCCTGGAAACCTTCCCCGACCTGTTCTGCCTGCCCCTGGGCGAGAGCTTTAGCGCCCTGACCGTG TCCGAGCACGTGTCCTACATCGTGACCAATCAGTACCTGATCAAGGGCATCAGCTACCCCGTGTCCACCA CAGTCGTGGGCCAGAGCCTGATCATCACCCAGACCGACAGCCAGACCAAGTGCGAGCTGACCCGGAACAT GCACACCACACACAGCATCACCGTGGCCCTGAACATCAGCCTGGAAAACTGCGCTTTCTGTCAGTCTGCC CTGCTGGAATACGACGATACCCAGGGCGTGATCAACATCATGTACATGCACGACAGCGACGACGTGCTGT TCGCCCTGGACCCCTACAACGAGGTGGTGGTGTCCAGCCCCCGGACCCACTACCTGATGCTGCTGAAGAA CGGCACCGTGCTGGAAGTGACCGACGTGGTGGTGGACGCCACCGACCTGTTGAATTTTGACCTTCTTAAG CTTGCGGGAGACGTCGAGTCCAACCCCGGGCCCATGTGCAGAAGGCCCGACTGCGGCTTCAGCTTCAGCC CTGGACCCGTGATCCTGCTGTGGTGCTGCCTGCTGCTGCCTATC GTGTCCTCTGCCGCCGTGTCTGTGGC CCCTACAGCCGCCGAGAAGGTGCCAGCCGAGTGCCCCGAGCTGACCAGAAGATGCCTGCTGGGCGAGGTG TTCGAGGGCGACAAGTACGAGAGCTGGCTGCGGCCCCTGGTCAACGTGACCGGCAGAGATGGCCCCCTGA GCCAGCTGATCCGGTACAGACCCGTGACCCCCGAGGCCGCCAATAGCGTGCTGCTGGACGAGGCCTTCCT GGATACCCTGGCCCTGCTGTACAACAACCCCGACCAGCTGAGAGCCCTGCTGACCCTGCTGTCCAGCGAC ACCGCCCCCAGATGGATGACCGTGATGCGGGGCTACAGCGAGTGTGGAGATGGCAGCCCTGCCGTGTACA CCTGCGTGGACGACCTGTGCAGAGGCTACGACCTGACCAGACTGAGCTACGGCCGGTCCATCTTCACAGA GCACGTGCTGGGCTTCGAGCTGGTGCCCCCCAGCCTGTTCAACGTGGTGGTGGCCATCCGGAACGAGGCC ACCAGAACCAACAGAGCCGTGCGGCTGCCTGTGTCTACAGCCGCTGCACCTGAGGGCATCACACTGTTCT ACGGCCTGTACAACGCCGTGAAAGAGTTCTGCCTCCGGCACCAGCTGGATCCCCCCCTGCTGAGACACCT GGACAAGTACTACGCCGGCCTGCCCCCAGAGCTGAAGCAGACCAGAGTGAACCTGCCCGCCCACAGCAGA TATGGCCCTCAGGCCGTGGACGCCAGATGATAAGCGGCCGCATACAGCAGCAATTGGCAAGCTGCTTACA TAGAACTCGCGGCGATTGGCATGCCGCCTTAAAATTTTTATTTTATTTTTCTTTTCTTTTCCGAATCGGA TTTTGTTTTTAATATTTCAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAGGGTCGGCATGGCATCT CCACCTCCTCGCGGTCCGACCTGGGCATCCGAAGGAGGACGCACGTCCAC TCGGATGGCTAAGGGAGAGC CACGTTTAAACACGTGATATCTGGCCTCATGGGCCTTCCTTTCACTGCCCGCTTTCCAGTCGGGAAACCT GTCGTGCCAGCTGCATTAACATGGTCATAGCTGTTTCCTTGCGTATTGGGCGCTCTCCGCTTCCTCGCTC ACTGACTCGCTGCGCTCGGTCGTTCGGGTAAAGCCTGGGGTGCCTAATGAGCAAAAGGCCAGCAAAAGGC CAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAA AATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAA GCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGG AAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTG GGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCA ACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGT AGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGTATTTGGTATC TGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCG CTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCC TTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGA TTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATC AATCTAAAGTATAT ATGAGTAAACTTGGTCTGACAGTTATTAGAAAAATTCATCCAGCAGACGATAAAACGCAATACGCTGGCT ATCCGGTGCCGCAATGCCATACAGCACCAGAAAACGATCCGCCCATTCGCCGCCCAGTTCTTCCGCAATA TCACGGGTGGCCAGCGCAATATCCTGATAACGATCCGCCACGCCCAGACGGCCGCAATCAATAAAGCCGC TAAAACGGCCATTTTCCACCATAATGTTCGGCAGGCACGCATCACCATGGGTCACCACCAGATCTTCGCC ATCCGGCATGCTCGCTTTCAGACGCGCAAACAGCTCTGCCGGTGCCAGGCCCTGATGTTCTTCATCCAGA TCATCCTGATCCACCAGGCCCGCTTCCATACGGGTACGCGCACGTTCAATACGATGTTTCGCCTGATGAT CAAACGGACAGGTCGCCGGGTCCAGGGTATGCAGACGACGCATGGCATCCGCCATAATGCTCACTTTTTC TGCCGGCGCCAGATGGCTAGACAGCAGATCCTGACCCGGCACTTCGCCCAGCAGCAGCCAATCACGGCCC GCTTCGGTCACCACATCCAGCACCGCCGCACACGGAACACCGGTGGTGGCCAGCCAGCTCAGACGCGCCG CTTCATCCTGCAGCTCGTTCAGCGCACCGCTCAGATCGGTTTTCACAAACAGCACCGGACGACCCTGCGC GCTCAGACGAAACACCGCCGCATCAGAGCAGCCAATGGTCTGCTGCGCCCAATCATAGCCAAACAGACGT TCCACCCACGCTGCCGGGCTACCCGCATGCAGGCCATCCTGTTCAATCATACTCTTCCTTTTTCAATATT ATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACA AATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTAAATTGTAAGCGTTAATATTTT GTTAAAAT TCGCGTTAAATTTTTGTTAAATCAGCTCATTTTTTAACCAATAGGCCGAAATCGGCAAAATCCCTTATAA ATCAAAAGAATAGACCGAGATAGGGTTGAGTGGCCGCTACAGGGCGCTCCCATTCGCCATTCAGGCTGCG CAACTGTTGGGAAGGGCGTTTCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTGC TGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACACGCGTAATACGACTCACTATAG Vector A533: SGP-gHsol-EV71-gl ATAGGCGGCGCATGAGAGAAGCCCAGACCAATTACCTACCCAAAATGGAGAAAGTTCACGTTGACATCGA GGAAGACAGCCCATTCCTCAGAGCTTTGCAGCGGAGCTTCCCGCAGTTTGAGGTAGAAGCCAAGCAGGTC ACTGATAATGACCATGCTAATGCCAGAGCGTTTTCGCATCTGGCTTCAAAACTGATCGAAACGGAGGTGG ACCCATCCGACACGATCCTTGACATTGGAAGTGCGCCCGCCCGCAGAATGTATTCTAAGCACAAGTATCA TTGTATCTGTCCGATGAGATGTGCGGAAGATCCGGACAGATTGTATAAGTATGCAACTAAGCTGAAGAAA AACTGTAAGGAAATAACTGATAAGGAATTGGACAAGAAAATGAAGGAGCTCGCCGCCGTCATGAGCGACC CTGACCTGGAAACTGAGACTATGTGCCTCCACGACGACGAGTCGTGTCGCTACGAAGGGCAAGTCGCTGT TTACCAGGATGTATACGCGGTTGACGGACCGACAAGTCTCTATCACCAAGCCAATAAGGGAGTTAGAGTC GCCTACTGGATAGGCTTTGACACCACCCCTTTTATGTTTAAGAACTTGGCTGGAGCATATCCATCATACT CTACCAACTGGGCCGACGAAACCGTGTTAACGGCTCGTAACATAGGCCTATGCAGCTCTGACGTTATGGA GCGGTCACGTAGAGGGATGTCCATTCTTAGAAAGAAGTATTTGAAACCATCCAACAATGTTCTATTCTCT GTTGGCTCGACCATCTACCACGAGAAGAGGGACTTACTGAGGAGCTGGCACCTGCCGTCTGTATTTCACT TACGTGGCAAGCAAAATTACACATGTCGGTGTGAGACTATAGTTAGTTGCGACGGGTACGTCGTTAAAAG AATAGCTATCAGTCCAGGCCTGTATGGGAAGCCTTCAGGCTATGCTGCTACGATGCACC GCGAGGGATTC TTGTGCTGCAAAGTGACAGACACATTGAACGGGGAGAGGGTCTCTTTTCCCGTGTGCACGTATGTGCCAG CTACATTGTGTGACCAAATGACTGGCATACTGGCAACAGATGTCAGTGCGGACGACGCGCAAAAACTGCT GGTTGGGCTCAACCAGCGTATAGTCGTCAACGGTCGCACCCAGAGAAACACCAATACCATGAAAAATTAC CTTTTGCCCGTAGTGGCCCAGGCATTTGCTAGGTGGGCAAAGGAATATAAGGAAGATCAAGAAGATGAAA GGCCACTAGGACTACGAGATAGACAGTTAGTCATGGGGTGTTGTTGGGCTTTTAGAAGGCACAAGATAAC ATCTATTTATAAGCGCCCGGATACCCAAACCATCATCAAAGTGAACAGCGATTTCCACTCATTCGTGCTG CCCAGGATAGGCAGTAACACATTGGAGATCGGGCTGAGAACAAGAATCAGGAAAATGTTAGAGGAGCACA AGGAGCCGTCACCTCTCATTACCGCCGAGGACGTACAAGAAGCTAAGTGCGCAGCCGATGAGGCTAAGGA GGTGCGTGAAGCCGAGGAGTTGCGCGCAGCTCTACCACCTTTGGCAGCTGATGTTGAGGAGCCCACTCTG GAAGCCGATGTCGACTTGATGTTACAAGAGGCTGGGGCCGGCTCAGTGGAGACACCTCGTGGCTTGATAA AGGTTACCAGCTACGATGGCGAGGACAAGATCGGCTCTTACGCTGTGCTTTCTCCGCAGGCTGTACTCAA GAGTGAAAAATTATCTTGCATCCACCCTCTCGCTGAACAAGTCATAGTGATAACACACTCTGGCCGAAAA GGGCGTTATGCCGTGGAACCATACCATGGTAAAGTAGTGGTGCCAGAGGGACATGCAATACCCGTCCAGG ACTTTCAAGCTCTGAGTGAAAGTGCCACCATTGTGTACAACGAACGTGAGTTCGTAAACAGGTAC CTGCA CCATATTGCCACACATGGAGGAGCGCTGAACACTGATGAAGAATATTACAAAACTGTCAAGCCCAGCGAG CACGACGGCGAATACCTGTACGACATCGACAGGAAACAGTGCGTCAAGAAAGAACTAGTCACTGGGCTAG GGCTCACAGGCGAGCTGGTGGATCCTCCCTTCCATGAATTCGCCTACGAGAGTCTGAGAACACGACCAGC CGCTCCTTACCAAGTACCAACCATAGGGGTGTATGGCGTGCCAGGATCAGGCAAGTCTGGCATCATTAAA AGCGCAGTCACCAAAAAAGATCTAGTGGTGAGCGCCAAGAAAGAAAACTGTGCAGAAATTATAAGGGACG TCAAGAAAATGAAAGGGCTGGACGTCAATGCCAGAACTGTGGACTCAGTGCTCTTGAATGGATGCAAACA CCCCGTAGAGACCCTGTATATTGACGAAGCTTTTGCTTGTCATGCAGGTACTCTCAGAGCGCTCATAGCC ATTATAAGACCTAAAAAGGCAGTGCTCTGCGGGGATCCCAAACAGTGCGGTTTTTTTAACATGATGTGCC TGAAAGTGCATTTTAACCACGAGATTTGCACACAAGTCTTCCACAAAAGCATCTCTCGCCGTTGCACTAA ATCTGTGACTTCGGTCGTCTCAACCTTGTTTTACGACAAAAAAATGAGAACGACGAATCCGAAAGAGACT AAGATTGTGATTGACACTACCGGCAGTACCAAACCTAAGCAGGACGATCTCATTCTCACTTGTTTCAGAG GGTGGGTGAAGCAGTTGCAAATAGATTACAAAGGCAACGAAATAATGACGGCAGCTGCCTCTCAAGGGCT GACCCGTAAAGGTGTGTATGCCGTTCGGTACAAGGTGAATGAAAATCCTCTGTACGCACCCACCTCAGAA CATGTGAACGTCCTACTGACCCGCACGGAGGACCGCATCGTGTGGAAAACACTAGCCGGCGACCCATGGA TAAAAACACTGACTGCCAAGTACCCTGGGAATTTCACTGCCACGATAGAGGAGTGGCAAGCAGAGCATGA TGCCATCATGAGGCACATCTTGGAGAGACCGGACCCTACCGACGTCTTCCAGAATAAGGCAAACGTGTGT TGGGCCAAGGCTTTAGTGCCGGTGCTGAAGACCGCTGGCATAGACATGACCACTGAACAATGGAACACTG TGGATTATTTTGAAACGGACAAAGCTCACTCAGCAGAGATAGTATTGAACCAACTATGCGTGAGGTTCTT TGGACTCGATCTGGACTCCGGTCTATTTTCTGCACCCACTGTTCCGTTATCCATTAGGAATAATCACTGG GATAACTCCCCGTCGCCTAACATGTACGGGCTGAATAAAGAAGTGGTCCGTCAGCTCTCTCGCAGGTACC CACAACTGCCTCGGGCAGTTGCCACTGGAAGAGTCTATGACATGAACACTGGTACACTGCGCAATTATGA TCCGCGCATAAACCTAGTACCTGTAAACAGAAGACTGCCTCATGCTTTAGTCCTCCACCATAATGAACAC CCACAGAGTGACTTTTCTTCATTCGTCAGCAAATTGAAGGGCAGAACTGTCCTGGTGGTCGGGGAAAAGT TGTCCGTCCCAGGCAAAATGGTTGACTGGTTGTCAGACCGGCCTGAGGCTACCTTCAGAGCTCGGCTGGA TTTAGGCATCCCAGGTGATGTGCCCAAATATGACATAATATTTGTTAATGTGAGGACCCCATATAAATAC CATCACTATCAGCAGTGTGAAGACCATGCCATTAAGCTTAGCATGTTGACCAAGAAAGCTTGTCTGCATC TGAATCCCGGCGGAACCTGTGTCAGCATAGGTTATGGTTACGCTGACAGGGCCAGCGAAAGCATCATTGG TGCTATAGCGCGGCAGTTCAAGTTTTCCCGGGTATGCAAACCGAAATCCTCACTTGAAGAGACGGAAGTT CTGTTT GTATTCATTGGGTACGATCGCAAGGCCCGTACGCACAATCCTTACAAGCTTTCATCAACCTTGA CCAACATTTATACAGGTTCCAGACTCCACGAAGCCGGATGTGCACCCTCATATCATGTGGTGCGAGGGGA TATTGCCACGGCCACCGAAGGAGTGATTATAAATGCTGCTAACAGCAAAGGACAACCTGGCGGAGGGGTG TGCGGAGCGCTGTATAAGAAATTCCCGGAAAGCTTCGATTTACAGCCGATCGAAGTAGGAAAAGCGCGAC TGGTCAAAGGTGCAGCTAAACATATCATTCATGCCGTAGGACCAAACTTCAACAAAGTTTCGGAGGTTGA AGGTGACAAACAGTTGGCAGAGGCTTATGAGTCCATCGCTAAGATTGTCAACGATAACAATTACAAGTCA GTAGCGATTCCACTGTTGTCCACCGGCATCTTTTCCGGGAACAAAGATCGACTAACCCAATCATTGAACC ATTTGCTGACAGCTTTAGACACCACTGATGCAGATGTAGCCATATACTGCAGGGACAAGAAATGGGAAAT GACTCTCAAGGAAGCAGTGGCTAGGAGAGAAGCAGTGGAGGAGATATGCATATCCGACGACTCTTCAGTG ACAGAACCTGATGCAGAGCTGGTGAGGGTGCATCCGAAGAGTTCTTTGGCTGGAAGGAAGGGCTACAGCA CAAGCGATGGCAAAACTTTCTCATATTTGGAAGGGACCAAGTTTCACCAGGCGGCCAAGGATATAGCAGA AATTAATGCCATGTGGCCCGTTGCAACGGAGGCCAATGAGCAGGTATGCATGTATATCCTCGGAGAAAGC ATGAGCAGTATTAGGTCGAAATGCCCCGTCGAAGAGTCGGAAGCCTCCACACCACCTAGCACGCTGCCTT GCTTGTGCATCCATGCCATGACTCCAGAAAGAGTACAGCGCCTAAAAGCCTCACGTCCAGAACAAATTAC TGTGTGCTCATC CTTTCCATTGCCGAAGTATAGAATCACTGGTGTGCAGAAGATCCAATGCTCCCAGCCT ATATTGTTCTCACCGAAAGTGCCTGCGTATATTCATCCAAGGAAGTATCTCGTGGAAACACCACCGGTAG ACGAGACTCCGGAGCCATCGGCAGAGAACCAATCCACAGAGGGGACACCTGAACAACCACCACTTATAAC CGAGGATGAGACCAGGACTAGAACGCCTGAGCCGATCATCATCGAAGAGGAAGAAGAGGATAGCATAAGT TTGCTGTCAGATGGCCCGACCCACCAGGTGCTGCAAGTCGAGGCAGACATTCACGGGCCGCCCTCTGTAT CTAGCTCATCCTGGTCCATTCCTCATGCATCCGACTTTGATGTGGACAGTTTATCCATACTTGACACCCT GGAGGGAGCTAGCGTGACCAGCGGGGCAACGTCAGCCGAGACTAACTCTTACTTCGCAAAGAGTATGGAG TTTCTGGCGCGACCGGTGCCTGCGCCTCGAACAGTATTCAGGAACCCTCCACATCCCGCTCCGCGCACAA GAACACCGTCACTTGCACCCAGCAGGGCCTGCTCGAGAACCAGCCTAGTTTCCACCCCGCCAGGCGTGAA TAGGGTGATCACTAGAGAGGAGCTCGAGGCGCTTACCCCGTCACGCACTCCTAGCAGGTCGGTCTCGAGA ACCAGCCTGGTCTCCAACCCGCCAGGCGTAAATAGGGTGATTACAAGAGAGGAGTTTGAGGCGTTCGTAG CACAACAACAATGACGGTTTGATGCGGGTGCATACATCTTTTCCTCCGACACCGGTCAAGGGCATTTACA ACAAAAATCAGTAAGGCAAACGGTGCTATCCGAAGTGGTGTTGGAGAGGACCGAATTGGAGATTTCGTAT GCCCCGCGCCTCGACCAAGAAAAAGAAGAATTACTACGCAAGAAATTACAGTTAAATCCCACACCTGCTA ACAGAAGCAGATACCAGT CCAGGAAGGTGGAGAACATGAAAGCCATAACAGCTAGACGTATTCTGCAAGG CCTAGGGCATTATTTGAAGGCAGAAGGAAAAGTGGAGTGCTACCGAACCCTGCATCCTGTTCCTTTGTAT TCATCTAGTGTGAACCGTGCCTTTTCAAGCCCCAAGGTCGCAGTGGAAGCCTGTAACGCCATGTTGAAAG AGAACTTTCCGACTGTGGCTTCTTACTGTATTATTCCAGAGTACGATGCCTATTTGGACATGGTTGACGG AGCTTCATGCTGCTTAGACACTGCCAGTTTTTGCCCTGCAAAGCTGCGCAGCTTTCCAAAGAAACACTCC TATTTGGAACCCACAATACGATCGGCAGTGCCTTCAGCGATCCAGAACACGCTCCAGAACGTCCTGGCAG CTGCCACAAAAAGAAATTGCAATGTCACGCAAATGAGAGAATTGCCCGTATTGGATTCGGCGGCCTTTAA TGTGGAATGCTTCAAGAAATATGCGTGTAATAATGAATATTGGGAAACGTTTAAAGAAAACCCCATCAGG CTTACTGAAGAAAACGTGGTAAATTACATTACCAAATTAAAAGGACCAAAAGCTGCTGCTCTTTTTGCGA AGACACATAATTTGAATATGTTGCAGGACATACCAATGGACAGGTTTGTAATGGACTTAAAGAGAGACGT GAAAGTGACTCCAGGAACAAAACATACTGAAGAACGGCCCAAGGTACAGGTGATCCAGGCTGCCGATCCG CTAGCAACAGCGTATCTGTGCGGAATCCACCGAGAGCTGGTTAGGAGATTAAATGCGGTCCTGCTTCCGA ACATTCATACACTGTTTGATATGTCGGCTGAAGACTTTGACGCTATTATAGCCGAGCACTTCCAGCCTGG GGATTGTGTTCTGGAAACTGACATCGCGTCGTTTGATAAAAGTGAGGACGACGCCATGGCTCTGACCGCG TTAATGATTCTGGAAGACTTAGGT GTGGACGCAGAGCTGTTGACGCTGATTGAGGCGGCTTTCGGCGAAA TTTCATCAATACATTTGCCCACTAAAACTAAATTTAAATTCGGAGCCATGATGAAATCTGGAATGTTCCT CACACTGTTTGTGAACACAGTCATTAACATTGTAATCGCAAGCAGAGTGTTGAGAGAACGGCTAACCGGA TCACCATGTGCAGCATTCATTGGAGATGACAATATCGTGAAAGGAGTCAAATCGGACAAATTAATGGCAG ACAGGTGCGCCACCTGGTTGAATATGGAAGTCAAGATTATAGATGCTGTGGTGGGCGAGAAAGCGCCTTA TTTCTGTGGAGGGTTTATTTTGTGTGACTCCGTGACCGGCACAGCGTGCCGTGTGGCAGACCCCCTAAAA AGGCTGTTTAAGCTTGGCAAACCTCTGGCAGCAGACGATGAACATGATGATGACAGGAGAAGGGCATTGC ATGAAGAGTCAACACGCTGGAACCGAGTGGGTATTCTTTCAGAGCTGTGCAAGGCAGTAGAATCAAGGTA TGAAACCGTAGGAACTTCCATCATAGTTATGGCCATGACTACTCTAGCTAGCAGTGTTAAATCATTCAGC TACCTGAGAGGGGCCCCTATAACTCTCTACGGCTAACCTGAATGGACTACGACATAGTCTAGTCCGCCAA GATGAGGCCTGGCCTGCCCTCCTACCTGATCATCCTGGCCGTGTGCCTGTTCAGCCACCTGCTGTCCAGC AGATACGGCGCCGAGGCCGTGAGCGAGCCCCTGGACAAGGCTTTCCACCTGCTGCTGAACACCTACGGCA GACCCATCCGGTTTCTGCGGGAGAACACCACCCAGTGCACCTACAACAGCAGCCTGCGGAACAGCACCGT CGTGAGAGAGAACGCCATCAGCTTCAACTTTTTCCAGAGCTACAACCAGTACTACGTGTTCCACATGCCC AGATGCCTGTTTGCCGGCCCTCTGGCCGAG CAGTTCCTGAACCAGGTGGACCTGACCGAGACACTGGAAA GATACCAGCAGCGGCTGAATACCTACGCCCTGGTGTCCAAGGACCTGGCCAGCTACCGGTCCTTTAGCCA GCAGCTCAAGGCTCAGGATAGCCTCGGCGAGCAGCCTACCACCGTGCCCCCTCCCATCGACCTGAGCATC CCCCACGTGTGGATGCCTCCCCAGACCACCCCTCACGGCTGGACCGAGAGCCACACCACCTCCGGCCTGC ACAGACCCCACTTCAACCAGACCTGCATCCTGTTCGACGGCCACGACCTGCTGTTTAGCACCGTGACCCC CTGCCTGCACCAGGGCTTCTACCTGATCGACGAGCTGAGATACGTGAAGATCACCCTGACCGAGGATTTC TTCGTGGTCACCGTGTCCATCGACGACGACACCCCCATGCTGCTGATCTTCGGCCACCTGCCCAGAGTGC TGTTCAAGGCCCCCTACCAGCGGGACAACTTCATCCTGCGGCAGACCGAGAAGCACGAGCTGCTGGTGCT GGTCAAGAAGGACCAGCTGAACCGGCACTCCTACCTGAAGGACCCCGACTTCCTGGACGCCGCCCTGGAC TTCAACTACCTGGACCTGAGCGCCCTGCTGAGAAACAGCTTCCACAGATACGCCGTGGACGTGCTGAAGT CCGGACGGTGCCAGATGCTCGATCGGCGGACCGTGGAGATGGCCTTCGCCTATGCCCTCGCCCTGTTCGC CGCTGCCAGACAGGAAGAGGCTGGCGCCCAGGTGTCAGTGCCCAGAGCCCTGGATAGACAGGCCGCCCTG CTGCAGATCCAGGAATTCATGATCACCTGCCTGAGCCAGACCCCCCCTAGAACCACCCTGCTGCTGTACC CCACAGCCGTGGATCTGGCCAAGAGGGCCCTGTGGACCCCCAACCAGATCACCGACATCACAAGCCTCGT GCGGCTCGTGTACATCCTGAGCAAGCAGAACCAGCA GCACCTGATCCCCCAGTGGGCCCTGAGACAGATC GCCGACTTCGCCCTGAAGCTGCACAAGACCCATCTGGCCAGCTTTCTGAGCGCCTTCGCCAGGCAGGAAC TGTACCTGATGGGCAGCCTGGTCCACAGCATGCTGGTGCATACCACCGAGCGGCGGGAGATCTTCATCGT GGAGACAGGCCTGTGTAGCCTGGCCGAGCTGTCCCACTTTACCCAGCTGCTGGCCCACCCTCACCACGAG TACCTGAGCGACCTGTACACCCCCTGCAGCAGCAGCGGCAGACGGGACCACAGCCTGGAACGGCTGACCA GACTGTTCCCCGATGCCACCGTGCCTGCTACAGTGCCTGCCGCCCTGTCCATCCTGTCCACCATGCAGCC CAGCACCCTGGAAACCTTCCCCGACCTGTTCTGCCTGCCCCTGGGCGAGAGCTTTAGCGCCCTGACCGTG TCCGAGCACGTGTCCTACATCGTGACCAATCAGTACCTGATCAAGGGCATCAGCTACCCCGTGTCCACCA CAGTCGTGGGCCAGAGCCTGATCATCACCCAGACCGACAGCCAGACCAAGTGCGAGCTGACCCGGAACAT GCACACCACACACAGCATCACCGTGGCCCTGAACATCAGCCTGGAAAACTGCGCTTTCTGTCAGTCTGCC CTGCTGGAATACGACGATACCCAGGGCGTGATCAACATCATGTACATGCACGACAGCGACGACGTGCTGT TCGCCCTGGACCCCTACAACGAGGTGGTGGTGTCCAGCCCCCGGACCCACTACCTGATGCTGCTGAAGAA CGGCACCGTGCTGGAAGTGACCGACGTGGTGGTGGACGCCACCGACTGATAATCTAGATTAAAACAGCTG TGGGTTGTTCCCACCCACAGGGCCCACTGGGCGCTAGCACTCTGATTTTACGAAATCCTTGTGCGCCTGT TTTATATCCCTTCCCTAATTCGAAACGTAGAAGCAATGCGCA CCACTGATCAATAGTAGGCGTAACGCGC CAGTTACGTCATGATCAAGCATATCTGTTCCCCCGGACTGAGTATCAATAGACTGCTTACGCGGTTGAAG GAGAAAACGTTCGTTATCCGGCTAACTACTTCGAGAAGCCCAGTAACACCATGGAAGCTGCAGGGTGTTT CGCTCAGCACTTCCCCCGTGTAGATCAGGTCGATGAGCCACTGCAATCCCCACAGGTGACTGTGGCAGTG GCTGCGTTGGCGGCCTGCCTATGGGGAGACCCATAGGACGCTCTAATGTGGACATGGTGCGAAGAGCCTA TTGAGCTAGTTAGTAGTCCTCCGGCCCCTGAATGCGGCTAATCCTAACTGCGGAGCACATGCCTTCAACC CAGAGGGTAGTGTGTCGTAATGGGCAACTCTGCAGCGGAACCGACTACTTTGGGTGTCCGTGTTTCTTTT TATTCTTATATTGGCTGCTTATGGTGACAATTACAGAATTGTTACCATATAGCTATTGGATTGGCCATCC GGTGTGTAATAGAGCTGTTATATACCTATTTGTTGGCTTTGTACCACTAACTTTAAAATCTATAACTACC CTCAACTTTATATTAACCCTCAATACAGTTGAACATGTGCAGAAGGCCCGACTGCGGCTTCAGCTTCAGC CCTGGACCCGTGATCCTGCTGTGGTGCTGCCTGCTGCTGCCTATCGTGTCCTCTGCCGCCGTGTCTGTGG CCCCTACAGCCGCCGAGAAGGTGCCAGCCGAGTGCCCCGAGCTGACCAGAAGATGCCTGCTGGGCGAGGT GTTCGAGGGCGACAAGTACGAGAGCTGGCTGCGGCCCCTGGTCAACGTGACCGGCAGAGATGGCCCCCTG AGCCAGCTGATCCGGTACAGACCCGTGACCCCCGAGGCCGCCAATAGCGTGCTGCTGGACGAGGCCTTCC TGGATACCCTGGCCCTGCTGTACAACAACCCCGACCAGCTGAGAGCCC TGCTGACCCTGCTGTCCAGCGA CACCGCCCCCAGATGGATGACCGTGATGCGGGGCTACAGCGAGTGTGGAGATGGCAGCCCTGCCGTGTAC ACCTGCGTGGACGACCTGTGCAGAGGCTACGACCTGACCAGACTGAGCTACGGCCGGTCCATCTTCACAG AGCACGTGCTGGGCTTCGAGCTGGTGCCCCCCAGCCTGTTCAACGTGGTGGTGGCCATCCGGAACGAGGC CACCAGAACCAACAGAGCCGTGCGGCTGCCTGTGTCTACAGCCGCTGCACCTGAGGGCATCACACTGTTC TACGGCCTGTACAACGCCGTGAAAGAGTTCTGCCTCCGGCACCAGCTGGATCCCCCCCTGCTGAGACACC TGGACAAGTACTACGCCGGCCTGCCCCCAGAGCTGAAGCAGACCAGAGTGAACCTGCCCGCCCACAGCAG ATATGGCCCTCAGGCCGTGGACGCCAGATGATAAGCGGCCGCATACAGCAGCAATTGGCAAGCTGCTTAC ATAGAACTCGCGGCGATTGGCATGCCGCCTTAAAATTTTTATTTTATTTTTCTTTTCTTTTCCGAATCGG ATTTTGTTTTTAATATTTCAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAGGGTCGGCATGGCATC TCCACCTCCTCGCGGTCCGACCTGGGCATCCGAAGGAGGACGCACGTCCACTCGGATGGCTAAGGGAGAG CCACGTTTAAACACGTGATATCTGGCCTCATGGGCCTTCCTTTCACTGCCCGCTTTCCAGTCGGGAAACC TGTCGTGCCAGCTGCATTAACATGGTCATAGCTGTTTCCTTGCGTATTGGGCGCTCTCCGCTTCCTCGCT CACTGACTCGCTGCGCTCGGTCGTTCGGGTAAAGCCTGGGGTGCCTAATGAGCAAAAGGCCAGCAAAAGG CCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCC CTGACGAGCATCACAA AAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGA AGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGG GAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCT GGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCC AACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATG TAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGTATTTGGTAT CTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACC GCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATC CTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAG ATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATA TATGAGTAAACTTGGTCTGACAGTTATTAGAAAAATTCATCCAGCAGACGATAAAACGCAATACGCTGGC TATCCGGTGCCGCAATGCCATACAGCACCAGAAAACGATCCGCCCATTCGCCGCCCAGTTCTTCCGCAAT ATCACGGGTGGCCAGCGCAATATCCTGATAACGATCCGCCACGCCCAGACGGCCGCAATCAATAAAGCCG CTAAAACGGCCATTTTCCACCATAATGTTCGGCAGGCACGCATCACCATGGGTCACCACC AGATCTTCGC CATCCGGCATGCTCGCTTTCAGACGCGCAAACAGCTCTGCCGGTGCCAGGCCCTGATGTTCTTCATCCAG ATCATCCTGATCCACCAGGCCCGCTTCCATACGGGTACGCGCACGTTCAATACGATGTTTCGCCTGATGA TCAAACGGACAGGTCGCCGGGTCCAGGGTATGCAGACGACGCATGGCATCCGCCATAATGCTCACTTTTT CTGCCGGCGCCAGATGGCTAGACAGCAGATCCTGACCCGGCACTTCGCCCAGCAGCAGCCAATCACGGCC CGCTTCGGTCACCACATCCAGCACCGCCGCACACGGAACACCGGTGGTGGCCAGCCAGCTCAGACGCGCC GCTTCATCCTGCAGCTCGTTCAGCGCACCGCTCAGATCGGTTTTCACAAACAGCACCGGACGACCCTGCG CGCTCAGACGAAACACCGCCGCATCAGAGCAGCCAATGGTCTGCTGCGCCCAATCATAGCCAAACAGACG TTCCACCCACGCTGCCGGGCTACCCGCATGCAGGCCATCCTGTTCAATCATACTCTTCCTTTTTCAATAT TATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAAC AAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTAAATTGTAAGCGTTAATATTTTGTTAAAA TTCGCGTTAAATTTTTGTTAAATCAGCTCATTTTTTAACCAATAGGCCGAAATCGGCAAAATCCCTTATA AATCAAAAGAATAGACCGAGATAGGGTTGAGTGGCCGCTACAGGGCGCTCCCATTCGCCATTCAGGCTGC GCAACTGTTGGGAAGGGCGTTTCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTG CTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACACGCGTAATACGACTCACTAT AG Vector A534: SGP-gl-EV71-gH ATAGGCGGCGCATGAGAGAAGCCCAGACCAATTACCTACCCAAAATGGAGAAAGTTCACGTTGACATCGA GGAAGACAGCCCATTCCTCAGAGCTTTGCAGCGGAGCTTCCCGCAGTTTGAGGTAGAAGCCAAGCAGGTC ACTGATAATGACCATGCTAATGCCAGAGCGTTTTCGCATCTGGCTTCAAAACTGATCGAAACGGAGGTGG ACCCATCCGACACGATCCTTGACATTGGAAGTGCGCCCGCCCGCAGAATGTATTCTAAGCACAAGTATCA TTGTATCTGTCCGATGAGATGTGCGGAAGATCCGGACAGATTGTATAAGTATGCAACTAAGCTGAAGAAA AACTGTAAGGAAATAACTGATAAGGAATTGGACAAGAAAATGAAGGAGCTCGCCGCCGTCATGAGCGACC CTGACCTGGAAACTGAGACTATGTGCCTCCACGACGACGAGTCGTGTCGCTACGAAGGGCAAGTCGCTGT TTACCAGGATGTATACGCGGTTGACGGACCGACAAGTCTCTATCACCAAGCCAATAAGGGAGTTAGAGTC GCCTACTGGATAGGCTTTGACACCACCCCTTTTATGTTTAAGAACTTGGCTGGAGCATATCCATCATACT CTACCAACTGGGCCGACGAAACCGTGTTAACGGCTCGTAACATAGGCCTATGCAGCTCTGACGTTATGGA GCGGTCACGTAGAGGGATGTCCATTCTTAGAAAGAAGTATTTGAAACCATCCAACAATGTTCTATTCTCT GTTGGCTCGACCATCTACCACGAGAAGAGGGACTTACTGAGGAGCTGGCACCTGCCGTCTGTATTTCACT TACGTGGCAAGCAAAATTACACATGTCGGTGTGAGACTATAGTTAGTTGCGACGGGTACGTCGTTAAAAG AATAGCTATCAGTCCAGGCCTGTATGGGAAGCCTTCAGGCTATGCTGCTACGATGCACCGCG AGGGATTC TTGTGCTGCAAAGTGACAGACACATTGAACGGGGAGAGGGTCTCTTTTCCCGTGTGCACGTATGTGCCAG CTACATTGTGTGACCAAATGACTGGCATACTGGCAACAGATGTCAGTGCGGACGACGCGCAAAAACTGCT GGTTGGGCTCAACCAGCGTATAGTCGTCAACGGTCGCACCCAGAGAAACACCAATACCATGAAAAATTAC CTTTTGCCCGTAGTGGCCCAGGCATTTGCTAGGTGGGCAAAGGAATATAAGGAAGATCAAGAAGATGAAA GGCCACTAGGACTACGAGATAGACAGTTAGTCATGGGGTGTTGTTGGGCTTTTAGAAGGCACAAGATAAC ATCTATTTATAAGCGCCCGGATACCCAAACCATCATCAAAGTGAACAGCGATTTCCACTCATTCGTGCTG CCCAGGATAGGCAGTAACACATTGGAGATCGGGCTGAGAACAAGAATCAGGAAAATGTTAGAGGAGCACA AGGAGCCGTCACCTCTCATTACCGCCGAGGACGTACAAGAAGCTAAGTGCGCAGCCGATGAGGCTAAGGA GGTGCGTGAAGCCGAGGAGTTGCGCGCAGCTCTACCACCTTTGGCAGCTGATGTTGAGGAGCCCACTCTG GAAGCCGATGTCGACTTGATGTTACAAGAGGCTGGGGCCGGCTCAGTGGAGACACCTCGTGGCTTGATAA AGGTTACCAGCTACGATGGCGAGGACAAGATCGGCTCTTACGCTGTGCTTTCTCCGCAGGCTGTACTCAA GAGTGAAAAATTATCTTGCATCCACCCTCTCGCTGAACAAGTCATAGTGATAACACACTCTGGCCGAAAA GGGCGTTATGCCGTGGAACCATACCATGGTAAAGTAGTGGTGCCAGAGGGACATGCAATACCCGTCCAGG ACTTTCAAGCTCTGAGTGAAAGTGCCACCATTGTGTACAACGAACGTGAGTTCGTAAACAGGTACCTG CA CCATATTGCCACACATGGAGGAGCGCTGAACACTGATGAAGAATATTACAAAACTGTCAAGCCCAGCGAG CACGACGGCGAATACCTGTACGACATCGACAGGAAACAGTGCGTCAAGAAAGAACTAGTCACTGGGCTAG GGCTCACAGGCGAGCTGGTGGATCCTCCCTTCCATGAATTCGCCTACGAGAGTCTGAGAACACGACCAGC CGCTCCTTACCAAGTACCAACCATAGGGGTGTATGGCGTGCCAGGATCAGGCAAGTCTGGCATCATTAAA AGCGCAGTCACCAAAAAAGATCTAGTGGTGAGCGCCAAGAAAGAAAACTGTGCAGAAATTATAAGGGACG TCAAGAAAATGAAAGGGCTGGACGTCAATGCCAGAACTGTGGACTCAGTGCTCTTGAATGGATGCAAACA CCCCGTAGAGACCCTGTATATTGACGAAGCTTTTGCTTGTCATGCAGGTACTCTCAGAGCGCTCATAGCC ATTATAAGACCTAAAAAGGCAGTGCTCTGCGGGGATCCCAAACAGTGCGGTTTTTTTAACATGATGTGCC TGAAAGTGCATTTTAACCACGAGATTTGCACACAAGTCTTCCACAAAAGCATCTCTCGCCGTTGCACTAA ATCTGTGACTTCGGTCGTCTCAACCTTGTTTTACGACAAAAAAATGAGAACGACGAATCCGAAAGAGACT AAGATTGTGATTGACACTACCGGCAGTACCAAACCTAAGCAGGACGATCTCATTCTCACTTGTTTCAGAG GGTGGGTGAAGCAGTTGCAAATAGATTACAAAGGCAACGAAATAATGACGGCAGCTGCCTCTCAAGGGCT GACCCGTAAAGGTGTGTATGCCGTTCGGTACAAGGTGAATGAAAATCCTCTGTACGCACCCACCTCAGAA CATGTGAACGTCCTACTGACCCGCACGGAGGACCGCATCGTGTGGAAAACACTAGCCGGCGACCCATGGA TAA AAACACTGACTGCCAAGTACCCTGGGAATTTCACTGCCACGATAGAGGAGTGGCAAGCAGAGCATGA TGCCATCATGAGGCACATCTTGGAGAGACCGGACCCTACCGACGTCTTCCAGAATAAGGCAAACGTGTGT TGGGCCAAGGCTTTAGTGCCGGTGCTGAAGACCGCTGGCATAGACATGACCACTGAACAATGGAACACTG TGGATTATTTTGAAACGGACAAAGCTCACTCAGCAGAGATAGTATTGAACCAACTATGCGTGAGGTTCTT TGGACTCGATCTGGACTCCGGTCTATTTTCTGCACCCACTGTTCCGTTATCCATTAGGAATAATCACTGG GATAACTCCCCGTCGCCTAACATGTACGGGCTGAATAAAGAAGTGGTCCGTCAGCTCTCTCGCAGGTACC CACAACTGCCTCGGGCAGTTGCCACTGGAAGAGTCTATGACATGAACACTGGTACACTGCGCAATTATGA TCCGCGCATAAACCTAGTACCTGTAAACAGAAGACTGCCTCATGCTTTAGTCCTCCACCATAATGAACAC CCACAGAGTGACTTTTCTTCATTCGTCAGCAAATTGAAGGGCAGAACTGTCCTGGTGGTCGGGGAAAAGT TGTCCGTCCCAGGCAAAATGGTTGACTGGTTGTCAGACCGGCCTGAGGCTACCTTCAGAGCTCGGCTGGA TTTAGGCATCCCAGGTGATGTGCCCAAATATGACATAATATTTGTTAATGTGAGGACCCCATATAAATAC CATCACTATCAGCAGTGTGAAGACCATGCCATTAAGCTTAGCATGTTGACCAAGAAAGCTTGTCTGCATC TGAATCCCGGCGGAACCTGTGTCAGCATAGGTTATGGTTACGCTGACAGGGCCAGCGAAAGCATCATTGG TGCTATAGCGCGGCAGTTCAAGTTTTCCCGGGTATGCAAACCGAAATCCTCACTTGAAGAGACGGAAGTT CTGTTTGTA TTCATTGGGTACGATCGCAAGGCCCGTACGCACAATCCTTACAAGCTTTCATCAACCTTGA CCAACATTTATACAGGTTCCAGACTCCACGAAGCCGGATGTGCACCCTCATATCATGTGGTGCGAGGGGA TATTGCCACGGCCACCGAAGGAGTGATTATAAATGCTGCTAACAGCAAAGGACAACCTGGCGGAGGGGTG TGCGGAGCGCTGTATAAGAAATTCCCGGAAAGCTTCGATTTACAGCCGATCGAAGTAGGAAAAGCGCGAC TGGTCAAAGGTGCAGCTAAACATATCATTCATGCCGTAGGACCAAACTTCAACAAAGTTTCGGAGGTTGA AGGTGACAAACAGTTGGCAGAGGCTTATGAGTCCATCGCTAAGATTGTCAACGATAACAATTACAAGTCA GTAGCGATTCCACTGTTGTCCACCGGCATCTTTTCCGGGAACAAAGATCGACTAACCCAATCATTGAACC ATTTGCTGACAGCTTTAGACACCACTGATGCAGATGTAGCCATATACTGCAGGGACAAGAAATGGGAAAT GACTCTCAAGGAAGCAGTGGCTAGGAGAGAAGCAGTGGAGGAGATATGCATATCCGACGACTCTTCAGTG ACAGAACCTGATGCAGAGCTGGTGAGGGTGCATCCGAAGAGTTCTTTGGCTGGAAGGAAGGGCTACAGCA CAAGCGATGGCAAAACTTTCTCATATTTGGAAGGGACCAAGTTTCACCAGGCGGCCAAGGATATAGCAGA AATTAATGCCATGTGGCCCGTTGCAACGGAGGCCAATGAGCAGGTATGCATGTATATCCTCGGAGAAAGC ATGAGCAGTATTAGGTCGAAATGCCCCGTCGAAGAGTCGGAAGCCTCCACACCACCTAGCACGCTGCCTT GCTTGTGCATCCATGCCATGACTCCAGAAAGAGTACAGCGCCTAAAAGCCTCACGTCCAGAACAAATTAC TGTGTGCTCATCCTT TCCATTGCCGAAGTATAGAATCACTGGTGTGCAGAAGATCCAATGCTCCCAGCCT ATATTGTTCTCACCGAAAGTGCCTGCGTATATTCATCCAAGGAAGTATCTCGTGGAAACACCACCGGTAG ACGAGACTCCGGAGCCATCGGCAGAGAACCAATCCACAGAGGGGACACCTGAACAACCACCACTTATAAC CGAGGATGAGACCAGGACTAGAACGCCTGAGCCGATCATCATCGAAGAGGAAGAAGAGGATAGCATAAGT TTGCTGTCAGATGGCCCGACCCACCAGGTGCTGCAAGTCGAGGCAGACATTCACGGGCCGCCCTCTGTAT CTAGCTCATCCTGGTCCATTCCTCATGCATCCGACTTTGATGTGGACAGTTTATCCATACTTGACACCCT GGAGGGAGCTAGCGTGACCAGCGGGGCAACGTCAGCCGAGACTAACTCTTACTTCGCAAAGAGTATGGAG TTTCTGGCGCGACCGGTGCCTGCGCCTCGAACAGTATTCAGGAACCCTCCACATCCCGCTCCGCGCACAA GAACACCGTCACTTGCACCCAGCAGGGCCTGCTCGAGAACCAGCCTAGTTTCCACCCCGCCAGGCGTGAA TAGGGTGATCACTAGAGAGGAGCTCGAGGCGCTTACCCCGTCACGCACTCCTAGCAGGTCGGTCTCGAGA ACCAGCCTGGTCTCCAACCCGCCAGGCGTAAATAGGGTGATTACAAGAGAGGAGTTTGAGGCGTTCGTAG CACAACAACAATGACGGTTTGATGCGGGTGCATACATCTTTTCCTCCGACACCGGTCAAGGGCATTTACA ACAAAAATCAGTAAGGCAAACGGTGCTATCCGAAGTGGTGTTGGAGAGGACCGAATTGGAGATTTCGTAT GCCCCGCGCCTCGACCAAGAAAAAGAAGAATTACTACGCAAGAAATTACAGTTAAATCCCACACCTGCTA ACAGAAGCAGATACCAGTCCA GGAAGGTGGAGAACATGAAAGCCATAACAGCTAGACGTATTCTGCAAGG CCTAGGGCATTATTTGAAGGCAGAAGGAAAAGTGGAGTGCTACCGAACCCTGCATCCTGTTCCTTTGTAT TCATCTAGTGTGAACCGTGCCTTTTCAAGCCCCAAGGTCGCAGTGGAAGCCTGTAACGCCATGTTGAAAG AGAACTTTCCGACTGTGGCTTCTTACTGTATTATTCCAGAGTACGATGCCTATTTGGACATGGTTGACGG AGCTTCATGCTGCTTAGACACTGCCAGTTTTTGCCCTGCAAAGCTGCGCAGCTTTCCAAAGAAACACTCC TATTTGGAACCCACAATACGATCGGCAGTGCCTTCAGCGATCCAGAACACGCTCCAGAACGTCCTGGCAG CTGCCACAAAAAGAAATTGCAATGTCACGCAAATGAGAGAATTGCCCGTATTGGATTCGGCGGCCTTTAA TGTGGAATGCTTCAAGAAATATGCGTGTAATAATGAATATTGGGAAACGTTTAAAGAAAACCCCATCAGG CTTACTGAAGAAAACGTGGTAAATTACATTACCAAATTAAAAGGACCAAAAGCTGCTGCTCTTTTTGCGA AGACACATAATTTGAATATGTTGCAGGACATACCAATGGACAGGTTTGTAATGGACTTAAAGAGAGACGT GAAAGTGACTCCAGGAACAAAACATACTGAAGAACGGCCCAAGGTACAGGTGATCCAGGCTGCCGATCCG CTAGCAACAGCGTATCTGTGCGGAATCCACCGAGAGCTGGTTAGGAGATTAAATGCGGTCCTGCTTCCGA ACATTCATACACTGTTTGATATGTCGGCTGAAGACTTTGACGCTATTATAGCCGAGCACTTCCAGCCTGG GGATTGTGTTCTGGAAACTGACATCGCGTCGTTTGATAAAAGTGAGGACGACGCCATGGCTCTGACCGCG TTAATGATTCTGGAAGACTTAGGTGTG GACGCAGAGCTGTTGACGCTGATTGAGGCGGCTTTCGGCGAAA TTTCATCAATACATTTGCCCACTAAAACTAAATTTAAATTCGGAGCCATGATGAAATCTGGAATGTTCCT CACACTGTTTGTGAACACAGTCATTAACATTGTAATCGCAAGCAGAGTGTTGAGAGAACGGCTAACCGGA TCACCATGTGCAGCATTCATTGGAGATGACAATATCGTGAAAGGAGTCAAATCGGACAAATTAATGGCAG ACAGGTGCGCCACCTGGTTGAATATGGAAGTCAAGATTATAGATGCTGTGGTGGGCGAGAAAGCGCCTTA TTTCTGTGGAGGGTTTATTTTGTGTGACTCCGTGACCGGCACAGCGTGCCGTGTGGCAGACCCCCTAAAA AGGCTGTTTAAGCTTGGCAAACCTCTGGCAGCAGACGATGAACATGATGATGACAGGAGAAGGGCATTGC ATGAAGAGTCAACACGCTGGAACCGAGTGGGTATTCTTTCAGAGCTGTGCAAGGCAGTAGAATCAAGGTA TGAAACCGTAGGAACTTCCATCATAGTTATGGCCATGACTACTCTAGCTAGCAGTGTTAAATCATTCAGC TACCTGAGAGGGGCCCCTATAACTCTCTACGGCTAACCTGAATGGACTACGACATAGTCTAGTCCGCCAA GATGTGCAGAAGGCCCGACTGCGGCTTCAGCTTCAGCCCTGGACCCGTGATCCTGCTGTGGTGCTGCCTG CTGCTGCCTATCGTGTCCTCTGCCGCCGTGTCTGTGGCCCCTACAGCCGCCGAGAAGGTGCCAGCCGAGT GCCCCGAGCTGACCAGAAGATGCCTGCTGGGCGAGGTGTTCGAGGGCGACAAGTACGAGAGCTGGCTGCG GCCCCTGGTCAACGTGACCGGCAGAGATGGCCCCCTGAGCCAGCTGATCCGGTACAGACCCGTGACCCCC GAGGCCGCCAATAGCGTGCTGCTGGACGAGGCC TTCCTGGATACCCTGGCCCTGCTGTACAACAACCCCG ACCAGCTGAGAGCCCTGCTGACCCTGCTGTCCAGCGACACCGCCCCCAGATGGATGACCGTGATGCGGGG CTACAGCGAGTGTGGAGATGGCAGCCCTGCCGTGTACACCTGCGTGGACGACCTGTGCAGAGGCTACGAC CTGACCAGACTGAGCTACGGCCGGTCCATCTTCACAGAGCACGTGCTGGGCTTCGAGCTGGTGCCCCCCA GCCTGTTCAACGTGGTGGTGGCCATCCGGAACGAGGCCACCAGAACCAACAGAGCCGTGCGGCTGCCTGT GTCTACAGCCGCTGCACCTGAGGGCATCACACTGTTCTACGGCCTGTACAACGCCGTGAAAGAGTTCTGC CTCCGGCACCAGCTGGATCCCCCCCTGCTGAGACACCTGGACAAGTACTACGCCGGCCTGCCCCCAGAGC TGAAGCAGACCAGAGTGAACCTGCCCGCCCACAGCAGATATGGCCCTCAGGCCGTGGACGCCAGATGATA ATCTAGATTAAAACAGCTGTGGGTTGTTCCCACCCACAGGGCCCACTGGGCGCTAGCACTCTGATTTTAC GAAATCCTTGTGCGCCTGTTTTATATCCCTTCCCTAATTCGAAACGTAGAAGCAATGCGCACCACTGATC AATAGTAGGCGTAACGCGCCAGTTACGTCATGATCAAGCATATCTGTTCCCCCGGACTGAGTATCAATAG ACTGCTTACGCGGTTGAAGGAGAAAACGTTCGTTATCCGGCTAACTACTTCGAGAAGCCCAGTAACACCA TGGAAGCTGCAGGGTGTTTCGCTCAGCACTTCCCCCGTGTAGATCAGGTCGATGAGCCACTGCAATCCCC ACAGGTGACTGTGGCAGTGGCTGCGTTGGCGGCCTGCCTATGGGGAGACCCATAGGACGCTCTAATGTGG ACATGGTGCGAAGAGCCTATTGAGCTAGTTAGTAGTCCT CCGGCCCCTGAATGCGGCTAATCCTAACTGC GGAGCACATGCCTTCAACCCAGAGGGTAGTGTGTCGTAATGGGCAACTCTGCAGCGGAACCGACTACTTT GGGTGTCCGTGTTTCTTTTTATTCTTATATTGGCTGCTTATGGTGACAATTACAGAATTGTTACCATATA GCTATTGGATTGGCCATCCGGTGTGTAATAGAGCTGTTATATACCTATTTGTTGGCTTTGTACCACTAAC TTTAAAATCTATAACTACCCTCAACTTTATATTAACCCTCAATACAGTTGAACATGAGGCCTGGCCTGCC CTCCTACCTGATCATCCTGGCCGTGTGCCTGTTCAGCCACCTGCTGTCCAGCAGATACGGCGCCGAGGCC GTGAGCGAGCCCCTGGACAAGGCTTTCCACCTGCTGCTGAACACCTACGGCAGACCCATCCGGTTTCTGC GGGAGAACACCACCCAGTGCACCTACAACAGCAGCCTGCGGAACAGCACCGTCGTGAGAGAGAACGCCAT CAGCTTCAACTTTTTCCAGAGCTACAACCAGTACTACGTGTTCCACATGCCCAGATGCCTGTTTGCCGGC CCTCTGGCCGAGCAGTTCCTGAACCAGGTGGACCTGACCGAGACACTGGAAAGATACCAGCAGCGGCTGA ATACCTACGCCCTGGTGTCCAAGGACCTGGCCAGCTACCGGTCCTTTAGCCAGCAGCTCAAGGCTCAGGA TAGCCTCGGCGAGCAGCCTACCACCGTGCCCCCTCCCATCGACCTGAGCATCCCCCACGTGTGGATGCCT CCCCAGACCACCCCTCACGGCTGGACCGAGAGCCACACCACCTCCGGCCTGCACAGACCCCACTTCAACC AGACCTGCATCCTGTTCGACGGCCACGACCTGCTGTTTAGCACCGTGACCCCCTGCCTGCACCAGGGCTT CTACCTGATCGACGAGCTGAGATACGTGAAGATCACCCTGACCGA GGATTTCTTCGTGGTCACCGTGTCC ATCGACGACGACACCCCCATGCTGCTGATCTTCGGCCACCTGCCCAGAGTGCTGTTCAAGGCCCCCTACC AGCGGGACAACTTCATCCTGCGGCAGACCGAGAAGCACGAGCTGCTGGTGCTGGTCAAGAAGGACCAGCT GAACCGGCACTCCTACCTGAAGGACCCCGACTTCCTGGACGCCGCCCTGGACTTCAACTACCTGGACCTG AGCGCCCTGCTGAGAAACAGCTTCCACAGATACGCCGTGGACGTGCTGAAGTCCGGACGGTGCCAGATGC TCGATCGGCGGACCGTGGAGATGGCCTTCGCCTATGCCCTCGCCCTGTTCGCCGCTGCCAGACAGGAAGA GGCTGGCGCCCAGGTGTCAGTGCCCAGAGCCCTGGATAGACAGGCCGCCCTGCTGCAGATCCAGGAATTC ATGATCACCTGCCTGAGCCAGACCCCCCCTAGAACCACCCTGCTGCTGTACCCCACAGCCGTGGATCTGG CCAAGAGGGCCCTGTGGACCCCCAACCAGATCACCGACATCACAAGCCTCGTGCGGCTCGTGTACATCCT GAGCAAGCAGAACCAGCAGCACCTGATCCCCCAGTGGGCCCTGAGACAGATCGCCGACTTCGCCCTGAAG CTGCACAAGACCCATCTGGCCAGCTTTCTGAGCGCCTTCGCCAGGCAGGAACTGTACCTGATGGGCAGCC TGGTCCACAGCATGCTGGTGCATACCACCGAGCGGCGGGAGATCTTCATCGTGGAGACAGGCCTGTGTAG CCTGGCCGAGCTGTCCCACTTTACCCAGCTGCTGGCCCACCCTCACCACGAGTACCTGAGCGACCTGTAC ACCCCCTGCAGCAGCAGCGGCAGACGGGACCACAGCCTGGAACGGCTGACCAGACTGTTCCCCGATGCCA CCGTGCCTGCTACAGTGCCTGCCGCCCTGTCCATCCTGTCCACCATGCAGC CCAGCACCCTGGAAACCTT CCCCGACCTGTTCTGCCTGCCCCTGGGCGAGAGCTTTAGCGCCCTGACCGTGTCCGAGCACGTGTCCTAC ATCGTGACCAATCAGTACCTGATCAAGGGCATCAGCTACCCCGTGTCCACCACAGTCGTGGGCCAGAGCC TGATCATCACCCAGACCGACAGCCAGACCAAGTGCGAGCTGACCCGGAACATGCACACCACACACAGCAT CACCGTGGCCCTGAACATCAGCCTGGAAAACTGCGCTTTCTGTCAGTCTGCCCTGCTGGAATACGACGAT ACCCAGGGCGTGATCAACATCATGTACATGCACGACAGCGACGACGTGCTGTTCGCCCTGGACCCCTACA ACGAGGTGGTGGTGTCCAGCCCCCGGACCCACTACCTGATGCTGCTGAAGAACGGCACCGTGCTGGAAGT GACCGACGTGGTGGTGGACGCCACCGACTGATAAGCGGCCGCATACAGCAGCAATTGGCAAGCTGCTTAC ATAGAACTCGCGGCGATTGGCATGCCGCCTTAAAATTTTTATTTTATTTTTCTTTTCTTTTCCGAATCGG ATTTTGTTTTTAATATTTCAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAGGGTCGGCATGGCATC TCCACCTCCTCGCGGTCCGACCTGGGCATCCGAAGGAGGACGCACGTCCACTCGGATGGCTAAGGGAGAG CCACGTTTAAACACGTGATATCTGGCCTCATGGGCCTTCCTTTCACTGCCCGCTTTCCAGTCGGGAAACC TGTCGTGCCAGCTGCATTAACATGGTCATAGCTGTTTCCTTGCGTATTGGGCGCTCTCCGCTTCCTCGCT CACTGACTCGCTGCGCTCGGTCGTTCGGGTAAAGCCTGGGGTGCCTAATGAGCAAAAGGCCAGCAAAAGG CCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTG ACGAGCATCACAA AAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGA AGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGG GAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCT GGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCC AACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATG TAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGTATTTGGTAT CTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACC GCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATC CTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAG ATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATA TATGAGTAAACTTGGTCTGACAGTTATTAGAAAAATTCATCCAGCAGACGATAAAACGCAATACGCTGGC TATCCGGTGCCGCAATGCCATACAGCACCAGAAAACGATCCGCCCATTCGCCGCCCAGTTCTTCCGCAAT ATCACGGGTGGCCAGCGCAATATCCTGATAACGATCCGCCACGCCCAGACGGCCGCAATCAATAAAGCCG CTAAAACGGCCATTTTCCACCATAATGTTCGGCAGGCACGCATCACCATGGGTCACCACCAGA TCTTCGC CATCCGGCATGCTCGCTTTCAGACGCGCAAACAGCTCTGCCGGTGCCAGGCCCTGATGTTCTTCATCCAG ATCATCCTGATCCACCAGGCCCGCTTCCATACGGGTACGCGCACGTTCAATACGATGTTTCGCCTGATGA TCAAACGGACAGGTCGCCGGGTCCAGGGTATGCAGACGACGCATGGCATCCGCCATAATGCTCACTTTTT CTGCCGGCGCCAGATGGCTAGACAGCAGATCCTGACCCGGCACTTCGCCCAGCAGCAGCCAATCACGGCC CGCTTCGGTCACCACATCCAGCACCGCCGCACACGGAACACCGGTGGTGGCCAGCCAGCTCAGACGCGCC GCTTCATCCTGCAGCTCGTTCAGCGCACCGCTCAGATCGGTTTTCACAAACAGCACCGGACGACCCTGCG CGCTCAGACGAAACACCGCCGCATCAGAGCAGCCAATGGTCTGCTGCGCCCAATCATAGCCAAACAGACG TTCCACCCACGCTGCCGGGCTACCCGCATGCAGGCCATCCTGTTCAATCATACTCTTCCTTTTTCAATAT TATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAAC AAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTAAATTGTAAGCGTTAATATTTTGTTAAAA TTCGCGTTAAATTTTTGTTAAATCAGCTCATTTTTTAACCAATAGGCCGAAATCGGCAAAATCCCTTATA AATCAAAAGAATAGACCGAGATAGGGTTGAGTGGCCGCTACAGGGCGCTCCCATTCGCCATTCAGGCTGC GCAACTGTTGGGAAGGGCGTTTCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTG CTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACACGCGTAATACGACTCACTATAG Vector A535: SGP-342-EV71-gHsol-2A-gl ATAGGCGGCGCATGAGAGAAGCCCAGACCAATTACCTACCCAAAATGGAGAAAGTTCACGTTGACATCGA GGAAGACAGCCCATTCCTCAGAGCTTTGCAGCGGAGCTTCCCGCAGTTTGAGGTAGAAGCCAAGCAGGTC ACTGATAATGACCATGCTAATGCCAGAGCGTTTTCGCATCTGGCTTCAAAACTGATCGAAACGGAGGTGG ACCCATCCGACACGATCCTTGACATTGGAAGTGCGCCCGCCCGCAGAATGTATTCTAAGCACAAGTATCA TTGTATCTGTCCGATGAGATGTGCGGAAGATCCGGACAGATTGTATAAGTATGCAACTAAGCTGAAGAAA AACTGTAAGGAAATAACTGATAAGGAATTGGACAAGAAAATGAAGGAGCTCGCCGCCGTCATGAGCGACC CTGACCTGGAAACTGAGACTATGTGCCTCCACGACGACGAGTCGTGTCGCTACGAAGGGCAAGTCGCTGT TTACCAGGATGTATACGCGGTTGACGGACCGACAAGTCTCTATCACCAAGCCAATAAGGGAGTTAGAGTC GCCTACTGGATAGGCTTTGACACCACCCCTTTTATGTTTAAGAACTTGGCTGGAGCATATCCATCATACT CTACCAACTGGGCCGACGAAACCGTGTTAACGGCTCGTAACATAGGCCTATGCAGCTCTGACGTTATGGA GCGGTCACGTAGAGGGATGTCCATTCTTAGAAAGAAGTATTTGAAACCATCCAACAATGTTCTATTCTCT GTTGGCTCGACCATCTACCACGAGAAGAGGGACTTACTGAGGAGCTGGCACCTGCCGTCTGTATTTCACT TACGTGGCAAGCAAAATTACACATGTCGGTGTGAGACTATAGTTAGTTGCGACGGGTACGTCGTTAAAAG AATAGCTATCAGTCCAGGCCTGTATGGGAAGCCTTCAGGCTATGCTGCTACG ATGCACCGCGAGGGATTC TTGTGCTGCAAAGTGACAGACACATTGAACGGGGAGAGGGTCTCTTTTCCCGTGTGCACGTATGTGCCAG CTACATTGTGTGACCAAATGACTGGCATACTGGCAACAGATGTCAGTGCGGACGACGCGCAAAAACTGCT GGTTGGGCTCAACCAGCGTATAGTCGTCAACGGTCGCACCCAGAGAAACACCAATACCATGAAAAATTAC CTTTTGCCCGTAGTGGCCCAGGCATTTGCTAGGTGGGCAAAGGAATATAAGGAAGATCAAGAAGATGAAA GGCCACTAGGACTACGAGATAGACAGTTAGTCATGGGGTGTTGTTGGGCTTTTAGAAGGCACAAGATAAC ATCTATTTATAAGCGCCCGGATACCCAAACCATCATCAAAGTGAACAGCGATTTCCACTCATTCGTGCTG CCCAGGATAGGCAGTAACACATTGGAGATCGGGCTGAGAACAAGAATCAGGAAAATGTTAGAGGAGCACA AGGAGCCGTCACCTCTCATTACCGCCGAGGACGTACAAGAAGCTAAGTGCGCAGCCGATGAGGCTAAGGA GGTGCGTGAAGCCGAGGAGTTGCGCGCAGCTCTACCACCTTTGGCAGCTGATGTTGAGGAGCCCACTCTG GAAGCCGATGTCGACTTGATGTTACAAGAGGCTGGGGCCGGCTCAGTGGAGACACCTCGTGGCTTGATAA AGGTTACCAGCTACGATGGCGAGGACAAGATCGGCTCTTACGCTGTGCTTTCTCCGCAGGCTGTACTCAA GAGTGAAAAATTATCTTGCATCCACCCTCTCGCTGAACAAGTCATAGTGATAACACACTCTGGCCGAAAA GGGCGTTATGCCGTGGAACCATACCATGGTAAAGTAGTGGTGCCAGAGGGACATGCAATACCCGTCCAGG ACTTTCAAGCTCTGAGTGAAAGTGCCACCATTGTGTACAACGAACGTGAGTTCGTAAA CAGGTACCTGCA CCATATTGCCACACATGGAGGAGCGCTGAACACTGATGAAGAATATTACAAAACTGTCAAGCCCAGCGAG CACGACGGCGAATACCTGTACGACATCGACAGGAAACAGTGCGTCAAGAAAGAACTAGTCACTGGGCTAG GGCTCACAGGCGAGCTGGTGGATCCTCCCTTCCATGAATTCGCCTACGAGAGTCTGAGAACACGACCAGC CGCTCCTTACCAAGTACCAACCATAGGGGTGTATGGCGTGCCAGGATCAGGCAAGTCTGGCATCATTAAA AGCGCAGTCACCAAAAAAGATCTAGTGGTGAGCGCCAAGAAAGAAAACTGTGCAGAAATTATAAGGGACG TCAAGAAAATGAAAGGGCTGGACGTCAATGCCAGAACTGTGGACTCAGTGCTCTTGAATGGATGCAAACA CCCCGTAGAGACCCTGTATATTGACGAAGCTTTTGCTTGTCATGCAGGTACTCTCAGAGCGCTCATAGCC ATTATAAGACCTAAAAAGGCAGTGCTCTGCGGGGATCCCAAACAGTGCGGTTTTTTTAACATGATGTGCC TGAAAGTGCATTTTAACCACGAGATTTGCACACAAGTCTTCCACAAAAGCATCTCTCGCCGTTGCACTAA ATCTGTGACTTCGGTCGTCTCAACCTTGTTTTACGACAAAAAAATGAGAACGACGAATCCGAAAGAGACT AAGATTGTGATTGACACTACCGGCAGTACCAAACCTAAGCAGGACGATCTCATTCTCACTTGTTTCAGAG GGTGGGTGAAGCAGTTGCAAATAGATTACAAAGGCAACGAAATAATGACGGCAGCTGCCTCTCAAGGGCT GACCCGTAAAGGTGTGTATGCCGTTCGGTACAAGGTGAATGAAAATCCTCTGTACGCACCCACCTCAGAA CATGTGAACGTCCTACTGACCCGCACGGAGGACCGCATCGTGTGGAAAACACTAGCCGGCGACC CATGGA TAAAAACACTGACTGCCAAGTACCCTGGGAATTTCACTGCCACGATAGAGGAGTGGCAAGCAGAGCATGA TGCCATCATGAGGCACATCTTGGAGAGACCGGACCCTACCGACGTCTTCCAGAATAAGGCAAACGTGTGT TGGGCCAAGGCTTTAGTGCCGGTGCTGAAGACCGCTGGCATAGACATGACCACTGAACAATGGAACACTG TGGATTATTTTGAAACGGACAAAGCTCACTCAGCAGAGATAGTATTGAACCAACTATGCGTGAGGTTCTT TGGACTCGATCTGGACTCCGGTCTATTTTCTGCACCCACTGTTCCGTTATCCATTAGGAATAATCACTGG GATAACTCCCCGTCGCCTAACATGTACGGGCTGAATAAAGAAGTGGTCCGTCAGCTCTCTCGCAGGTACC CACAACTGCCTCGGGCAGTTGCCACTGGAAGAGTCTATGACATGAACACTGGTACACTGCGCAATTATGA TCCGCGCATAAACCTAGTACCTGTAAACAGAAGACTGCCTCATGCTTTAGTCCTCCACCATAATGAACAC CCACAGAGTGACTTTTCTTCATTCGTCAGCAAATTGAAGGGCAGAACTGTCCTGGTGGTCGGGGAAAAGT TGTCCGTCCCAGGCAAAATGGTTGACTGGTTGTCAGACCGGCCTGAGGCTACCTTCAGAGCTCGGCTGGA TTTAGGCATCCCAGGTGATGTGCCCAAATATGACATAATATTTGTTAATGTGAGGACCCCATATAAATAC CATCACTATCAGCAGTGTGAAGACCATGCCATTAAGCTTAGCATGTTGACCAAGAAAGCTTGTCTGCATC TGAATCCCGGCGGAACCTGTGTCAGCATAGGTTATGGTTACGCTGACAGGGCCAGCGAAAGCATCATTGG TGCTATAGCGCGGCAGTTCAAGTTTTCCCGGGTATGCAAACCGAAATCCTCACTTGAAGAGACGGAAGTT CTGTTTGTATTCATTGGGTACGATCGCAAGGCCCGTACGCACAATCCTTACAAGCTTTCATCAACCTTGA CCAACATTTATACAGGTTCCAGACTCCACGAAGCCGGATGTGCACCCTCATATCATGTGGTGCGAGGGGA TATTGCCACGGCCACCGAAGGAGTGATTATAAATGCTGCTAACAGCAAAGGACAACCTGGCGGAGGGGTG TGCGGAGCGCTGTATAAGAAATTCCCGGAAAGCTTCGATTTACAGCCGATCGAAGTAGGAAAAGCGCGAC TGGTCAAAGGTGCAGCTAAACATATCATTCATGCCGTAGGACCAAACTTCAACAAAGTTTCGGAGGTTGA AGGTGACAAACAGTTGGCAGAGGCTTATGAGTCCATCGCTAAGATTGTCAACGATAACAATTACAAGTCA GTAGCGATTCCACTGTTGTCCACCGGCATCTTTTCCGGGAACAAAGATCGACTAACCCAATCATTGAACC ATTTGCTGACAGCTTTAGACACCACTGATGCAGATGTAGCCATATACTGCAGGGACAAGAAATGGGAAAT GACTCTCAAGGAAGCAGTGGCTAGGAGAGAAGCAGTGGAGGAGATATGCATATCCGACGACTCTTCAGTG ACAGAACCTGATGCAGAGCTGGTGAGGGTGCATCCGAAGAGTTCTTTGGCTGGAAGGAAGGGCTACAGCA CAAGCGATGGCAAAACTTTCTCATATTTGGAAGGGACCAAGTTTCACCAGGCGGCCAAGGATATAGCAGA AATTAATGCCATGTGGCCCGTTGCAACGGAGGCCAATGAGCAGGTATGCATGTATATCCTCGGAGAAAGC ATGAGCAGTATTAGGTCGAAATGCCCCGTCGAAGAGTCGGAAGCCTCCACACCACCTAGCACGCTGCCTT GCTTGTGCATCCATGCCATGACTCCAGAAAGAGTACAGCGCCTAAAAGCCTCACGTCCAGAACAAATTAC TGTGT GCTCATCCTTTCCATTGCCGAAGTATAGAATCACTGGTGTGCAGAAGATCCAATGCTCCCAGCCT ATATTGTTCTCACCGAAAGTGCCTGCGTATATTCATCCAAGGAAGTATCTCGTGGAAACACCACCGGTAG ACGAGACTCCGGAGCCATCGGCAGAGAACCAATCCACAGAGGGGACACCTGAACAACCACCACTTATAAC CGAGGATGAGACCAGGACTAGAACGCCTGAGCCGATCATCATCGAAGAGGAAGAAGAGGATAGCATAAGT TTGCTGTCAGATGGCCCGACCCACCAGGTGCTGCAAGTCGAGGCAGACATTCACGGGCCGCCCTCTGTAT CTAGCTCATCCTGGTCCATTCCTCATGCATCCGACTTTGATGTGGACAGTTTATCCATACTTGACACCCT GGAGGGAGCTAGCGTGACCAGCGGGGCAACGTCAGCCGAGACTAACTCTTACTTCGCAAAGAGTATGGAG TTTCTGGCGCGACCGGTGCCTGCGCCTCGAACAGTATTCAGGAACCCTCCACATCCCGCTCCGCGCACAA GAACACCGTCACTTGCACCCAGCAGGGCCTGCTCGAGAACCAGCCTAGTTTCCACCCCGCCAGGCGTGAA TAGGGTGATCACTAGAGAGGAGCTCGAGGCGCTTACCCCGTCACGCACTCCTAGCAGGTCGGTCTCGAGA ACCAGCCTGGTCTCCAACCCGCCAGGCGTAAATAGGGTGATTACAAGAGAGGAGTTTGAGGCGTTCGTAG CACAACAACAATGACGGTTTGATGCGGGTGCATACATCTTTTCCTCCGACACCGGTCAAGGGCATTTACA ACAAAAATCAGTAAGGCAAACGGTGCTATCCGAAGTGGTGTTGGAGAGGACCGAATTGGAGATTTCGTAT GCCCCGCGCCTCGACCAAGAAAAAGAAGAATTACTACGCAAGAAATTACAGTTAAATCCCACACCTGCTA ACAGAAGCAGA TACCAGTCCAGGAAGGTGGAGAACATGAAAGCCATAACAGCTAGACGTATTCTGCAAGG CCTAGGGCATTATTTGAAGGCAGAAGGAAAAGTGGAGTGCTACCGAACCCTGCATCCTGTTCCTTTGTAT TCATCTAGTGTGAACCGTGCCTTTTCAAGCCCCAAGGTCGCAGTGGAAGCCTGTAACGCCATGTTGAAAG AGAACTTTCCGACTGTGGCTTCTTACTGTATTATTCCAGAGTACGATGCCTATTTGGACATGGTTGACGG AGCTTCATGCTGCTTAGACACTGCCAGTTTTTGCCCTGCAAAGCTGCGCAGCTTTCCAAAGAAACACTCC TATTTGGAACCCACAATACGATCGGCAGTGCCTTCAGCGATCCAGAACACGCTCCAGAACGTCCTGGCAG CTGCCACAAAAAGAAATTGCAATGTCACGCAAATGAGAGAATTGCCCGTATTGGATTCGGCGGCCTTTAA TGTGGAATGCTTCAAGAAATATGCGTGTAATAATGAATATTGGGAAACGTTTAAAGAAAACCCCATCAGG CTTACTGAAGAAAACGTGGTAAATTACATTACCAAATTAAAAGGACCAAAAGCTGCTGCTCTTTTTGCGA AGACACATAATTTGAATATGTTGCAGGACATACCAATGGACAGGTTTGTAATGGACTTAAAGAGAGACGT GAAAGTGACTCCAGGAACAAAACATACTGAAGAACGGCCCAAGGTACAGGTGATCCAGGCTGCCGATCCG CTAGCAACAGCGTATCTGTGCGGAATCCACCGAGAGCTGGTTAGGAGATTAAATGCGGTCCTGCTTCCGA ACATTCATACACTGTTTGATATGTCGGCTGAAGACTTTGACGCTATTATAGCCGAGCACTTCCAGCCTGG GGATTGTGTTCTGGAAACTGACATCGCGTCGTTTGATAAAAGTGAGGACGACGCCATGGCTCTGACCGCG TTAATGATTCTGGAAGA CTTAGGTGTGGACGCAGAGCTGTTGACGCTGATTGAGGCGGCTTTCGGCGAAA TTTCATCAATACATTTGCCCACTAAAACTAAATTTAAATTCGGAGCCATGATGAAATCTGGAATGTTCCT CACACTGTTTGTGAACACAGTCATTAACATTGTAATCGCAAGCAGAGTGTTGAGAGAACGGCTAACCGGA TCACCATGTGCAGCATTCATTGGAGATGACAATATCGTGAAAGGAGTCAAATCGGACAAATTAATGGCAG ACAGGTGCGCCACCTGGTTGAATATGGAAGTCAAGATTATAGATGCTGTGGTGGGCGAGAAAGCGCCTTA TTTCTGTGGAGGGTTTATTTTGTGTGACTCCGTGACCGGCACAGCGTGCCGTGTGGCAGACCCCCTAAAA AGGCTGTTTAAGCTTGGCAAACCTCTGGCAGCAGACGATGAACATGATGATGACAGGAGAAGGGCATTGC ATGAAGAGTCAACACGCTGGAACCGAGTGGGTATTCTTTCAGAGCTGTGCAAGGCAGTAGAATCAAGGTA TGAAACCGTAGGAACTTCCATCATAGTTATGGCCATGACTACTCTAGCTAGCAGTGTTAAATCATTCAGC TACCTGAGAGGGGCCCCTATAACTCTCTACGGCTAACCTGAATGGACTACGACATAGTCTAGTCCGCCAA GCTATTCCAGAAGTAGTGAGGAGGCTTTTTTGGAGGCCTAGGCTTTTGCAAAAAGCTTGTATATCCATTT TCGGATCTGATCAAGAGACAGGATGAGGATCGTTTCGCATGATTGAATAAGATGGATTGCACGTAGGTTC TCCGGCCGCTTGGGTGGAGAGGCTATTCGGCTATGACTGGGCACAACTGACAATCGGCTGCTCTGATGCC GCCGTGATCCGGTTGTCAGCGCAGGGGCGCCCGGTTCTTTTTGTCAAGACCGACCTGTCCGGTGCCCTGA ATGAACTGAAGGACGAGGCAGCG CGGCTATCGTGGCTGGCCACGACGGGCGTTCCTTGCGCAGTCTAGAC TGGCGCGCCAAACCTGCAGGTTAAAACAGCTGTGGGTTGTTCCCACCCACAGGGCCCACTGGGCGCTAGC ACTCTGATTTTACGAAATCCTTGTGCGCCTGTTTTATATCCCTTCCCTAATTCGAAACGTAGAAGCAATG CGCACCACTGATCAATAGTAGGCGTAACGCGCCAGTTACGTCATGATCAAGCATATCTGTTCCCCCGGAC TGAGTATCAATAGACTGCTTACGCGGTTGAAGGAGAAAACGTTCGTTATCCGGCTAACTACTTCGAGAAG CCCAGTAACACCATGGAAGCTGCAGGGTGTTTCGCTCAGCACTTCCCCCGTGTAGATCAGGTCGATGAGC CACTGCAATCCCCACAGGTGACTGTGGCAGTGGCTGCGTTGGCGGCCTGCCTATGGGGAGACCCATAGGA CGCTCTAATGTGGACATGGTGCGAAGAGCCTATTGAGCTAGTTAGTAGTCCTCCGGCCCCTGAATGCGGC TAATCCTAACTGCGGAGCACATGCCTTCAACCCAGAGGGTAGTGTGTCGTAATGGGCAACTCTGCAGCGG AACCGACTACTTTGGGTGTCCGTGTTTCTTTTTATTCTTATATTGGCTGCTTATGGTGACAATTACAGAA TTGTTACCATATAGCTATTGGATTGGCCATCCGGTGTGTAATAGAGCTGTTATATACCTATTTGTTGGCT TTGTACCACTAACTTTAAAATCTATAACTACCCTCAACTTTATATTAACCCTCAATACAGTTGAACATGA GGCCTGGCCTGCCCTCCTACCTGATCATCCTGGCCGTGTGCCTGTTCAGCCACCTGCTGTCCAGCAGATA CGGCGCCGAGGCCGTGAGCGAGCCCCTGGACAAGGCTTTCCACCTGCTGCTGAACACCTACGGCAGACCC ATCCGGTTTCTGCGGGAGAACACCACCCA GTGCACCTACAACAGCAGCCTGCGGAACAGCACCGTCGTGA GAGAGAACGCCATCAGCTTCAACTTTTTCCAGAGCTACAACCAGTACTACGTGTTCCACATGCCCAGATG CCTGTTTGCCGGCCCTCTGGCCGAGCAGTTCCTGAACCAGGTGGACCTGACCGAGACACTGGAAAGATAC CAGCAGCGGCTGAATACCTACGCCCTGGTGTCCAAGGACCTGGCCAGCTACCGGTCCTTTAGCCAGCAGC TCAAGGCTCAGGATAGCCTCGGCGAGCAGCCTACCACCGTGCCCCCTCCCATCGACCTGAGCATCCCCCA CGTGTGGATGCCTCCCCAGACCACCCCTCACGGCTGGACCGAGAGCCACACCACCTCCGGCCTGCACAGA CCCCACTTCAACCAGACCTGCATCCTGTTCGACGGCCACGACCTGCTGTTTAGCACCGTGACCCCCTGCC TGCACCAGGGCTTCTACCTGATCGACGAGCTGAGATACGTGAAGATCACCCTGACCGAGGATTTCTTCGT GGTCACCGTGTCCATCGACGACGACACCCCCATGCTGCTGATCTTCGGCCACCTGCCCAGAGTGCTGTTC AAGGCCCCCTACCAGCGGGACAACTTCATCCTGCGGCAGACCGAGAAGCACGAGCTGCTGGTGCTGGTCA AGAAGGACCAGCTGAACCGGCACTCCTACCTGAAGGACCCCGACTTCCTGGACGCCGCCCTGGACTTCAA CTACCTGGACCTGAGCGCCCTGCTGAGAAACAGCTTCCACAGATACGCCGTGGACGTGCTGAAGTCCGGA CGGTGCCAGATGCTCGATCGGCGGACCGTGGAGATGGCCTTCGCCTATGCCCTCGCCCTGTTCGCCGCTG CCAGACAGGAAGAGGCTGGCGCCCAGGTGTCAGTGCCCAGAGCCCTGGATAGACAGGCCGCCCTGCTGCA GATCCAGGAATTCATGATCACCTGCCTGAGCCAGA CCCCCCCTAGAACCACCCTGCTGCTGTACCCCACA GCCGTGGATCTGGCCAAGAGGGCCCTGTGGACCCCCAACCAGATCACCGACATCACAAGCCTCGTGCGGC TCGTGTACATCCTGAGCAAGCAGAACCAGCAGCACCTGATCCCCCAGTGGGCCCTGAGACAGATCGCCGA CTTCGCCCTGAAGCTGCACAAGACCCATCTGGCCAGCTTTCTGAGCGCCTTCGCCAGGCAGGAACTGTAC CTGATGGGCAGCCTGGTCCACAGCATGCTGGTGCATACCACCGAGCGGCGGGAGATCTTCATCGTGGAGA CAGGCCTGTGTAGCCTGGCCGAGCTGTCCCACTTTACCCAGCTGCTGGCCCACCCTCACCACGAGTACCT GAGCGACCTGTACACCCCCTGCAGCAGCAGCGGCAGACGGGACCACAGCCTGGAACGGCTGACCAGACTG TTCCCCGATGCCACCGTGCCTGCTACAGTGCCTGCCGCCCTGTCCATCCTGTCCACCATGCAGCCCAGCA CCCTGGAAACCTTCCCCGACCTGTTCTGCCTGCCCCTGGGCGAGAGCTTTAGCGCCCTGACCGTGTCCGA GCACGTGTCCTACATCGTGACCAATCAGTACCTGATCAAGGGCATCAGCTACCCCGTGTCCACCACAGTC GTGGGCCAGAGCCTGATCATCACCCAGACCGACAGCCAGACCAAGTGCGAGCTGACCCGGAACATGCACA CCACACACAGCATCACCGTGGCCCTGAACATCAGCCTGGAAAACTGCGCTTTCTGTCAGTCTGCCCTGCT GGAATACGACGATACCCAGGGCGTGATCAACATCATGTACATGCACGACAGCGACGACGTGCTGTTCGCC CTGGACCCCTACAACGAGGTGGTGGTGTCCAGCCCCCGGACCCACTACCTGATGCTGCTGAAGAACGGCA CCGTGCTGGAAGTGACCGACGTGGTGGTGGACGCCACCGAC CTGTTGAATTTTGACCTTCTTAAGCTTGC GGGAGACGTCGAGTCCAACCCCGGGCCCATGTGCAGAAGGCCCGACTGCGGCTTCAGCTTCAGCCCTGGA CCCGTGATCCTGCTGTGGTGCTGCCTGCTGCTGCCTATCGTGTCCTCTGCCGCCGTGTCTGTGGCCCCTA CAGCCGCCGAGAAGGTGCCAGCCGAGTGCCCCGAGCTGACCAGAAGATGCCTGCTGGGCGAGGTGTTCGA GGGCGACAAGTACGAGAGCTGGCTGCGGCCCCTGGTCAACGTGACCGGCAGAGATGGCCCCCTGAGCCAG CTGATCCGGTACAGACCCGTGACCCCCGAGGCCGCCAATAGCGTGCTGCTGGACGAGGCCTTCCTGGATA CCCTGGCCCTGCTGTACAACAACCCCGACCAGCTGAGAGCCCTGCTGACCCTGCTGTCCAGCGACACCGC CCCCAGATGGATGACCGTGATGCGGGGCTACAGCGAGTGTGGAGATGGCAGCCCTGCCGTGTACACCTGC GTGGACGACCTGTGCAGAGGCTACGACCTGACCAGACTGAGCTACGGCCGGTCCATCTTCACAGAGCACG TGCTGGGCTTCGAGCTGGTGCCCCCCAGCCTGTTCAACGTGGTGGTGGCCATCCGGAACGAGGCCACCAG AACCAACAGAGCCGTGCGGCTGCCTGTGTCTACAGCCGCTGCACCTGAGGGCATCACACTGTTCTACGGC CTGTACAACGCCGTGAAAGAGTTCTGCCTCCGGCACCAGCTGGATCCCCCCCTGCTGAGACACCTGGACA AGTACTACGCCGGCCTGCCCCCAGAGCTGAAGCAGACCAGAGTGAACCTGCCCGCCCACAGCAGATATGG CCCTCAGGCCGTGGACGCCAGATGATAAGCGGCCGCATACAGCAGCAATTGGCAAGCTGCTTACATAGAA CTCGCGGCGATTGGCATGCCGCCTTAAAATTTTTATTTTATTTTTCT TTTCTTTTCCGAATCGGATTTTG TTTTTAATATTTCAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAGGGTCGGCATGGCATCTCCACC TCCTCGCGGTCCGACCTGGGCATCCGAAGGAGGACGCACGTCCACTCGGATGGCTAAGGGAGAGCCACGT TTAAACACGTGATATCTGGCCTCATGGGCCTTCCTTTCACTGCCCGCTTTCCAGTCGGGAAACCTGTCGT GCCAGCTGCATTAACATGGTCATAGCTGTTTCCTTGCGTATTGGGCGCTCTCCGCTTCCTCGCTCACTGA CTCGCTGCGCTCGGTCGTTCGGGTAAAGCCTGGGGTGCCTAATGAGCAAAAGGCCAGCAAAAGGCCAGGA ACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCG ACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCC CTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCG TGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTG TGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCG GTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCG GTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGTATTTGGTATCTGCGC TCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGT AGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATC TCAAGAAGATCCTTTGA TCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATC AAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAG TAAACTTGGTCTGACAGTTATTAGAAAAATTCATCCAGCAGACGATAAAACGCAATACGCTGGCTATCCG GTGCCGCAATGCCATACAGCACCAGAAAACGATCCGCCCATTCGCCGCCCAGTTCTTCCGCAATATCACG GGTGGCCAGCGCAATATCCTGATAACGATCCGCCACGCCCAGACGGCCGCAATCAATAAAGCCGCTAAAA CGGCCATTTTCCACCATAATGTTCGGCAGGCACGCATCACCATGGGTCACCACCAGATCTTCGCCATCCG GCATGCTCGCTTTCAGACGCGCAAACAGCTCTGCCGGTGCCAGGCCCTGATGTTCTTCATCCAGATCATC CTGATCCACCAGGCCCGCTTCCATACGGGTACGCGCACGTTCAATACGATGTTTCGCCTGATGATCAAAC GGACAGGTCGCCGGGTCCAGGGTATGCAGACGACGCATGGCATCCGCCATAATGCTCACTTTTTCTGCCG GCGCCAGATGGCTAGACAGCAGATCCTGACCCGGCACTTCGCCCAGCAGCAGCCAATCACGGCCCGCTTC GGTCACCACATCCAGCACCGCCGCACACGGAACACCGGTGGTGGCCAGCCAGCTCAGACGCGCCGCTTCA TCCTGCAGCTCGTTCAGCGCACCGCTCAGATCGGTTTTCACAAACAGCACCGGACGACCCTGCGCGCTCA GACGAAACACCGCCGCATCAGAGCAGCCAATGGTCTGCTGCGCCCAATCATAGCCAAACAGACGTTCCAC CCACGCTGCCGGGCTACCCGCATGCAGGCCATCCTGTTCAATCATACTCTTCCTTTTTC AATATTATTGA AGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAAATAG GGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTAAATTGTAAGCGTTAATATTTTGTTAAAATTCGCG TTAAATTTTTGTTAAATCAGCTCATTTTTTAACCAATAGGCCGAAATCGGCAAAATCCCTTATAAATCAA AAGAATAGACCGAGATAGGGTTGAGTGGCCGCTACAGGGCGCTCCCATTCGCCATTCAGGCTGCGCAACT GTTGGGAAGGGCGTTTCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTGCTGCAA GGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACACGCGTAATACGACTCACTATAG Vector A536: SGP-342-EV71-gHsol-EMCV-gl ATAGGCGGCGCATGAGAGAAGCCCAGACCAATTACCTACCCAAAATGGAGAAAGTTCACGTTGACATCGA GGAAGACAGCCCATTCCTCAGAGCTTTGCAGCGGAGCTTCCCGCAGTTTGAGGTAGAAGCCAAGCAGGTC ACTGATAATGACCATGCTAATGCCAGAGCGTTTTCGCATCTGGCTTCAAAACTGATCGAAACGGAGGTGG ACCCATCCGACACGATCCTTGACATTGGAAGTGCGCCCGCCCGCAGAATGTATTCTAAGCACAAGTATCA TTGTATCTGTCCGATGAGATGTGCGGAAGATCCGGACAGATTGTATAAGTATGCAACTAAGCTGAAGAAA AACTGTAAGGAAATAACTGATAAGGAATTGGACAAGAAAATGAAGGAGCTCGCCGCCGTCATGAGCGACC CTGACCTGGAAACTGAGACTATGTGCCTCCACGACGACGAGTCGTGTCGCTACGAAGGGCAAGTCGCTGT TTACCAGGATGTATACGCGGTTGACGGACCGACAAGTCTCTATCACCAAGCCAATAAGGGAGTTAGAGTC GCCTACTGGATAGGCTTTGACACCACCCCTTTTATGTTTAAGAACTTGGCTGGAGCATATCCATCATACT CTACCAACTGGGCCGACGAAACCGTGTTAACGGCTCGTAACATAGGCCTATGCAGCTCTGACGTTATGGA GCGGTCACGTAGAGGGATGTCCATTCTTAGAAAGAAGTATTTGAAACCATCCAACAATGTTCTATTCTCT GTTGGCTCGACCATCTACCACGAGAAGAGGGACTTACTGAGGAGCTGGCACCTGCCGTCTGTATTTCACT TACGTGGCAAGCAAAATTACACATGTCGGTGTGAGACTATAGTTAGTTGCGACGGGTACGTCGTTAAAAG AATAGCTATCAGTCCAGGCCTGTATGGGAAGCCTTCAGGCTATGCTGCTA CGATGCACCGCGAGGGATTC TTGTGCTGCAAAGTGACAGACACATTGAACGGGGAGAGGGTCTCTTTTCCCGTGTGCACGTATGTGCCAG CTACATTGTGTGACCAAATGACTGGCATACTGGCAACAGATGTCAGTGCGGACGACGCGCAAAAACTGCT GGTTGGGCTCAACCAGCGTATAGTCGTCAACGGTCGCACCCAGAGAAACACCAATACCATGAAAAATTAC CTTTTGCCCGTAGTGGCCCAGGCATTTGCTAGGTGGGCAAAGGAATATAAGGAAGATCAAGAAGATGAAA GGCCACTAGGACTACGAGATAGACAGTTAGTCATGGGGTGTTGTTGGGCTTTTAGAAGGCACAAGATAAC ATCTATTTATAAGCGCCCGGATACCCAAACCATCATCAAAGTGAACAGCGATTTCCACTCATTCGTGCTG CCCAGGATAGGCAGTAACACATTGGAGATCGGGCTGAGAACAAGAATCAGGAAAATGTTAGAGGAGCACA AGGAGCCGTCACCTCTCATTACCGCCGAGGACGTACAAGAAGCTAAGTGCGCAGCCGATGAGGCTAAGGA GGTGCGTGAAGCCGAGGAGTTGCGCGCAGCTCTACCACCTTTGGCAGCTGATGTTGAGGAGCCCACTCTG GAAGCCGATGTCGACTTGATGTTACAAGAGGCTGGGGCCGGCTCAGTGGAGACACCTCGTGGCTTGATAA AGGTTACCAGCTACGATGGCGAGGACAAGATCGGCTCTTACGCTGTGCTTTCTCCGCAGGCTGTACTCAA GAGTGAAAAATTATCTTGCATCCACCCTCTCGCTGAACAAGTCATAGTGATAACACACTCTGGCCGAAAA GGGCGTTATGCCGTGGAACCATACCATGGTAAAGTAGTGGTGCCAGAGGGACATGCAATACCCGTCCAGG ACTTTCAAGCTCTGAGTGAAAGTGCCACCATTGTGTACAACGAACGTGAGTTCGTA AACAGGTACCTGCA CCATATTGCCACACATGGAGGAGCGCTGAACACTGATGAAGAATATTACAAAACTGTCAAGCCCAGCGAG CACGACGGCGAATACCTGTACGACATCGACAGGAAACAGTGCGTCAAGAAAGAACTAGTCACTGGGCTAG GGCTCACAGGCGAGCTGGTGGATCCTCCCTTCCATGAATTCGCCTACGAGAGTCTGAGAACACGACCAGC CGCTCCTTACCAAGTACCAACCATAGGGGTGTATGGCGTGCCAGGATCAGGCAAGTCTGGCATCATTAAA AGCGCAGTCACCAAAAAAGATCTAGTGGTGAGCGCCAAGAAAGAAAACTGTGCAGAAATTATAAGGGACG TCAAGAAAATGAAAGGGCTGGACGTCAATGCCAGAACTGTGGACTCAGTGCTCTTGAATGGATGCAAACA CCCCGTAGAGACCCTGTATATTGACGAAGCTTTTGCTTGTCATGCAGGTACTCTCAGAGCGCTCATAGCC ATTATAAGACCTAAAAAGGCAGTGCTCTGCGGGGATCCCAAACAGTGCGGTTTTTTTAACATGATGTGCC TGAAAGTGCATTTTAACCACGAGATTTGCACACAAGTCTTCCACAAAAGCATCTCTCGCCGTTGCACTAA ATCTGTGACTTCGGTCGTCTCAACCTTGTTTTACGACAAAAAAATGAGAACGACGAATCCGAAAGAGACT AAGATTGTGATTGACACTACCGGCAGTACCAAACCTAAGCAGGACGATCTCATTCTCACTTGTTTCAGAG GGTGGGTGAAGCAGTTGCAAATAGATTACAAAGGCAACGAAATAATGACGGCAGCTGCCTCTCAAGGGCT GACCCGTAAAGGTGTGTATGCCGTTCGGTACAAGGTGAATGAAAATCCTCTGTACGCACCCACCTCAGAA CATGTGAACGTCCTACTGACCCGCACGGAGGACCGCATCGTGTGGAAAACACTAGCCGGCGA CCCATGGA TAAAAACACTGACTGCCAAGTACCCTGGGAATTTCACTGCCACGATAGAGGAGTGGCAAGCAGAGCATGA TGCCATCATGAGGCACATCTTGGAGAGACCGGACCCTACCGACGTCTTCCAGAATAAGGCAAACGTGTGT TGGGCCAAGGCTTTAGTGCCGGTGCTGAAGACCGCTGGCATAGACATGACCACTGAACAATGGAACACTG TGGATTATTTTGAAACGGACAAAGCTCACTCAGCAGAGATAGTATTGAACCAACTATGCGTGAGGTTCTT TGGACTCGATCTGGACTCCGGTCTATTTTCTGCACCCACTGTTCCGTTATCCATTAGGAATAATCACTGG GATAACTCCCCGTCGCCTAACATGTACGGGCTGAATAAAGAAGTGGTCCGTCAGCTCTCTCGCAGGTACC CACAACTGCCTCGGGCAGTTGCCACTGGAAGAGTCTATGACATGAACACTGGTACACTGCGCAATTATGA TCCGCGCATAAACCTAGTACCTGTAAACAGAAGACTGCCTCATGCTTTAGTCCTCCACCATAATGAACAC CCACAGAGTGACTTTTCTTCATTCGTCAGCAAATTGAAGGGCAGAACTGTCCTGGTGGTCGGGGAAAAGT TGTCCGTCCCAGGCAAAATGGTTGACTGGTTGTCAGACCGGCCTGAGGCTACCTTCAGAGCTCGGCTGGA TTTAGGCATCCCAGGTGATGTGCCCAAATATGACATAATATTTGTTAATGTGAGGACCCCATATAAATAC CATCACTATCAGCAGTGTGAAGACCATGCCATTAAGCTTAGCATGTTGACCAAGAAAGCTTGTCTGCATC TGAATCCCGGCGGAACCTGTGTCAGCATAGGTTATGGTTACGCTGACAGGGCCAGCGAAAGCATCATTGG TGCTATAGCGCGGCAGTTCAAGTTTTCCCGGGTATGCAAACCGAAATCCTCACTTGAAGAGACGGAAG TT CTGTTTGTATTCATTGGGTACGATCGCAAGGCCCGTACGCACAATCCTTACAAGCTTTCATCAACCTTGA CCAACATTTATACAGGTTCCAGACTCCACGAAGCCGGATGTGCACCCTCATATCATGTGGTGCGAGGGGA TATTGCCACGGCCACCGAAGGAGTGATTATAAATGCTGCTAACAGCAAAGGACAACCTGGCGGAGGGGTG TGCGGAGCGCTGTATAAGAAATTCCCGGAAAGCTTCGATTTACAGCCGATCGAAGTAGGAAAAGCGCGAC TGGTCAAAGGTGCAGCTAAACATATCATTCATGCCGTAGGACCAAACTTCAACAAAGTTTCGGAGGTTGA AGGTGACAAACAGTTGGCAGAGGCTTATGAGTCCATCGCTAAGATTGTCAACGATAACAATTACAAGTCA GTAGCGATTCCACTGTTGTCCACCGGCATCTTTTCCGGGAACAAAGATCGACTAACCCAATCATTGAACC ATTTGCTGACAGCTTTAGACACCACTGATGCAGATGTAGCCATATACTGCAGGGACAAGAAATGGGAAAT GACTCTCAAGGAAGCAGTGGCTAGGAGAGAAGCAGTGGAGGAGATATGCATATCCGACGACTCTTCAGTG ACAGAACCTGATGCAGAGCTGGTGAGGGTGCATCCGAAGAGTTCTTTGGCTGGAAGGAAGGGCTACAGCA CAAGCGATGGCAAAACTTTCTCATATTTGGAAGGGACCAAGTTTCACCAGGCGGCCAAGGATATAGCAGA AATTAATGCCATGTGGCCCGTTGCAACGGAGGCCAATGAGCAGGTATGCATGTATATCCTCGGAGAAAGC ATGAGCAGTATTAGGTCGAAATGCCCCGTCGAAGAGTCGGAAGCCTCCACACCACCTAGCACGCTGCCTT TGT GCTTGTGCATCCATGCCATGACTCCAGAAAGAGTACAGCGCCTAAAAGCCTCACGTCCAGAACAAATTAC GTGCTCATCCTTTCCATTGCCGAAGTATAGAATCACTGGTGTGCAGAAGATCCAATGCTCCCAGCCT ATATTGTTCTCACCGAAAGTGCCTGCGTATATTCATCCAAGGAAGTATCTCGTGGAAACACCACCGGTAG ACGAGACTCCGGAGCCATCGGCAGAGAACCAATCCACAGAGGGGACACCTGAACAACCACCACTTATAAC CGAGGATGAGACCAGGACTAGAACGCCTGAGCCGATCATCATCGAAGAGGAAGAAGAGGATAGCATAAGT TTGCTGTCAGATGGCCCGACCCACCAGGTGCTGCAAGTCGAGGCAGACATTCACGGGCCGCCCTCTGTAT CTAGCTCATCCTGGTCCATTCCTCATGCATCCGACTTTGATGTGGACAGTTTATCCATACTTGACACCCT GGAGGGAGCTAGCGTGACCAGCGGGGCAACGTCAGCCGAGACTAACTCTTACTTCGCAAAGAGTATGGAG TTTCTGGCGCGACCGGTGCCTGCGCCTCGAACAGTATTCAGGAACCCTCCACATCCCGCTCCGCGCACAA GAACACCGTCACTTGCACCCAGCAGGGCCTGCTCGAGAACCAGCCTAGTTTCCACCCCGCCAGGCGTGAA TAGGGTGATCACTAGAGAGGAGCTCGAGGCGCTTACCCCGTCACGCACTCCTAGCAGGTCGGTCTCGAGA ACCAGCCTGGTCTCCAACCCGCCAGGCGTAAATAGGGTGATTACAAGAGAGGAGTTTGAGGCGTTCGTAG CACAACAACAATGACGGTTTGATGCGGGTGCATACATCTTTTCCTCCGACACCGGTCAAGGGCATTTACA ACAAAAATCAGTAAGGCAAACGGTGCTATCCGAAGTGGTGTTGGAGAGGACCGAATTGGAGATTTCGTAT GCCCCGCGCCTCGACCAAGAAAAAGAAGAATTACTACGCAAGAAATTACAGTTAAATCCCACACCTGCTA ACAGAAGCA GATACCAGTCCAGGAAGGTGGAGAACATGAAAGCCATAACAGCTAGACGTATTCTGCAAGG CCTAGGGCATTATTTGAAGGCAGAAGGAAAAGTGGAGTGCTACCGAACCCTGCATCCTGTTCCTTTGTAT TCATCTAGTGTGAACCGTGCCTTTTCAAGCCCCAAGGTCGCAGTGGAAGCCTGTAACGCCATGTTGAAAG AGAACTTTCCGACTGTGGCTTCTTACTGTATTATTCCAGAGTACGATGCCTATTTGGACATGGTTGACGG AGCTTCATGCTGCTTAGACACTGCCAGTTTTTGCCCTGCAAAGCTGCGCAGCTTTCCAAAGAAACACTCC TATTTGGAACCCACAATACGATCGGCAGTGCCTTCAGCGATCCAGAACACGCTCCAGAACGTCCTGGCAG CTGCCACAAAAAGAAATTGCAATGTCACGCAAATGAGAGAATTGCCCGTATTGGATTCGGCGGCCTTTAA TGTGGAATGCTTCAAGAAATATGCGTGTAATAATGAATATTGGGAAACGTTTAAAGAAAACCCCATCAGG CTTACTGAAGAAAACGTGGTAAATTACATTACCAAATTAAAAGGACCAAAAGCTGCTGCTCTTTTTGCGA AGACACATAATTTGAATATGTTGCAGGACATACCAATGGACAGGTTTGTAATGGACTTAAAGAGAGACGT GAAAGTGACTCCAGGAACAAAACATACTGAAGAACGGCCCAAGGTACAGGTGATCCAGGCTGCCGATCCG CTAGCAACAGCGTATCTGTGCGGAATCCACCGAGAGCTGGTTAGGAGATTAAATGCGGTCCTGCTTCCGA ACATTCATACACTGTTTGATATGTCGGCTGAAGACTTTGACGCTATTATAGCCGAGCACTTCCAGCCTGG GGATTGTGTTCTGGAAACTGACATCGCGTCGTTTGATAAAAGTGAGGACGACGCCATGGCTCTGACCGCG TTAATGATTCTGGAA GACTTAGGTGTGGACGCAGAGCTGTTGACGCTGATTGAGGCGGCTTTCGGCGAAA TTTCATCAATACATTTGCCCACTAAAACTAAATTTAAATTCGGAGCCATGATGAAATCTGGAATGTTCCT CACACTGTTTGTGAACACAGTCATTAACATTGTAATCGCAAGCAGAGTGTTGAGAGAACGGCTAACCGGA TCACCATGTGCAGCATTCATTGGAGATGACAATATCGTGAAAGGAGTCAAATCGGACAAATTAATGGCAG ACAGGTGCGCCACCTGGTTGAATATGGAAGTCAAGATTATAGATGCTGTGGTGGGCGAGAAAGCGCCTTA TTTCTGTGGAGGGTTTATTTTGTGTGACTCCGTGACCGGCACAGCGTGCCGTGTGGCAGACCCCCTAAAA AGGCTGTTTAAGCTTGGCAAACCTCTGGCAGCAGACGATGAACATGATGATGACAGGAGAAGGGCATTGC ATGAAGAGTCAACACGCTGGAACCGAGTGGGTATTCTTTCAGAGCTGTGCAAGGCAGTAGAATCAAGGTA TGAAACCGTAGGAACTTCCATCATAGTTATGGCCATGACTACTCTAGCTAGCAGTGTTAAATCATTCAGC TACCTGAGAGGGGCCCCTATAACTCTCTACGGCTAACCTGAATGGACTACGACATAGTCTAGTCCGCCAA GCTATTCCAGAAGTAGTGAGGAGGCTTTTTTGGAGGCCTAGGCTTTTGCAAAAAGCTTGTATATCCATTT TCGGATCTGATCAAGAGACAGGATGAGGATCGTTTCGCATGATTGAATAAGATGGATTGCACGTAGGTTC TCCGGCCGCTTGGGTGGAGAGGCTATTCGGCTATGACTGGGCACAACTGACAATCGGCTGCTCTGATGCC GCCGTGATCCGGTTGTCAGCGCAGGGGCGCCCGGTTCTTTTTGTCAAGACCGACCTGTCCGGTGCCCTGA ATGAACTGAAGGACGAGGCAG CGCGGCTATCGTGGCTGGCCACGACGGGCGTTCCTTGCGCAGTCTAGAC TGGCGCGCCAAACCTGCAGGTTAAAACAGCTGTGGGTTGTTCCCACCCACAGGGCCCACTGGGCGCTAGC ACTCTGATTTTACGAAATCCTTGTGCGCCTGTTTTATATCCCTTCCCTAATTCGAAACGTAGAAGCAATG CGCACCACTGATCAATAGTAGGCGTAACGCGCCAGTTACGTCATGATCAAGCATATCTGTTCCCCCGGAC TGAGTATCAATAGACTGCTTACGCGGTTGAAGGAGAAAACGTTCGTTATCCGGCTAACTACTTCGAGAAG CCCAGTAACACCATGGAAGCTGCAGGGTGTTTCGCTCAGCACTTCCCCCGTGTAGATCAGGTCGATGAGC CACTGCAATCCCCACAGGTGACTGTGGCAGTGGCTGCGTTGGCGGCCTGCCTATGGGGAGACCCATAGGA CGCTCTAATGTGGACATGGTGCGAAGAGCCTATTGAGCTAGTTAGTAGTCCTCCGGCCCCTGAATGCGGC TAATCCTAACTGCGGAGCACATGCCTTCAACCCAGAGGGTAGTGTGTCGTAATGGGCAACTCTGCAGCGG AACCGACTACTTTGGGTGTCCGTGTTTCTTTTTATTCTTATATTGGCTGCTTATGGTGACAATTACAGAA TTGTTACCATATAGCTATTGGATTGGCCATCCGGTGTGTAATAGAGCTGTTATATACCTATTTGTTGGCT TTGTACCACTAACTTTAAAATCTATAACTACCCTCAACTTTATATTAACCCTCAATACAGTTGAACATGA GGCCTGGCCTGCCCTCCTACCTGATCATCCTGGCCGTGTGCCTGTTCAGCCACCTGCTGTCCAGCAGATA CGGCGCCGAGGCCGTGAGCGAGCCCCTGGACAAGGCTTTCCACCTGCTGCTGAACACCTACGGCAGACCC ATCCGGTTTCTGCGGGAGAACACCACC CAGTGCACCTACAACAGCAGCCTGCGGAACAGCACCGTCGTGA GAGAGAACGCCATCAGCTTCAACTTTTTCCAGAGCTACAACCAGTACTACGTGTTCCACATGCCCAGATG CCTGTTTGCCGGCCCTCTGGCCGAGCAGTTCCTGAACCAGGTGGACCTGACCGAGACACTGGAAAGATAC CAGCAGCGGCTGAATACCTACGCCCTGGTGTCCAAGGACCTGGCCAGCTACCGGTCCTTTAGCCAGCAGC TCAAGGCTCAGGATAGCCTCGGCGAGCAGCCTACCACCGTGCCCCCTCCCATCGACCTGAGCATCCCCCA CGTGTGGATGCCTCCCCAGACCACCCCTCACGGCTGGACCGAGAGCCACACCACCTCCGGCCTGCACAGA CCCCACTTCAACCAGACCTGCATCCTGTTCGACGGCCACGACCTGCTGTTTAGCACCGTGACCCCCTGCC TGCACCAGGGCTTCTACCTGATCGACGAGCTGAGATACGTGAAGATCACCCTGACCGAGGATTTCTTCGT GGTCACCGTGTCCATCGACGACGACACCCCCATGCTGCTGATCTTCGGCCACCTGCCCAGAGTGCTGTTC AAGGCCCCCTACCAGCGGGACAACTTCATCCTGCGGCAGACCGAGAAGCACGAGCTGCTGGTGCTGGTCA AGAAGGACCAGCTGAACCGGCACTCCTACCTGAAGGACCCCGACTTCCTGGACGCCGCCCTGGACTTCAA CTACCTGGACCTGAGCGCCCTGCTGAGAAACAGCTTCCACAGATACGCCGTGGACGTGCTGAAGTCCGGA CGGTGCCAGATGCTCGATCGGCGGACCGTGGAGATGGCCTTCGCCTATGCCCTCGCCCTGTTCGCCGCTG CCAGACAGGAAGAGGCTGGCGCCCAGGTGTCAGTGCCCAGAGCCCTGGATAGACAGGCCGCCCTGCTGCA GATCCAGGAATTCATGATCACCTGCCTGAGCCA GACCCCCCCTAGAACCACCCTGCTGCTGTACCCCACA GCCGTGGATCTGGCCAAGAGGGCCCTGTGGACCCCCAACCAGATCACCGACATCACAAGCCTCGTGCGGC TCGTGTACATCCTGAGCAAGCAGAACCAGCAGCACCTGATCCCCCAGTGGGCCCTGAGACAGATCGCCGA CTTCGCCCTGAAGCTGCACAAGACCCATCTGGCCAGCTTTCTGAGCGCCTTCGCCAGGCAGGAACTGTAC CTGATGGGCAGCCTGGTCCACAGCATGCTGGTGCATACCACCGAGCGGCGGGAGATCTTCATCGTGGAGA CAGGCCTGTGTAGCCTGGCCGAGCTGTCCCACTTTACCCAGCTGCTGGCCCACCCTCACCACGAGTACCT GAGCGACCTGTACACCCCCTGCAGCAGCAGCGGCAGACGGGACCACAGCCTGGAACGGCTGACCAGACTG TTCCCCGATGCCACCGTGCCTGCTACAGTGCCTGCCGCCCTGTCCATCCTGTCCACCATGCAGCCCAGCA CCCTGGAAACCTTCCCCGACCTGTTCTGCCTGCCCCTGGGCGAGAGCTTTAGCGCCCTGACCGTGTCCGA GCACGTGTCCTACATCGTGACCAATCAGTACCTGATCAAGGGCATCAGCTACCCCGTGTCCACCACAGTC GTGGGCCAGAGCCTGATCATCACCCAGACCGACAGCCAGACCAAGTGCGAGCTGACCCGGAACATGCACA CCACACACAGCATCACCGTGGCCCTGAACATCAGCCTGGAAAACTGCGCTTTCTGTCAGTCTGCCCTGCT GGAATACGACGATACCCAGGGCGTGATCAACATCATGTACATGCACGACAGCGACGACGTGCTGTTCGCC CTGGACCCCTACAACGAGGTGGTGGTGTCCAGCCCCCGGACCCACTACCTGATGCTGCTGAAGAACGGCA CCGTGCTGGAAGTGACCGACGTGGTGGTGGACGCCACCG ACTGATAACGCCGGCGCCCCCCCCTAACGTT ACTGGCCGAAGCCGCTTGGAATAAGGCCGGTGTGCGTTTGTCTATATGTTATTTTCCACCATATTGCCGT CTTTTGGCAATGTGAGGGCCCGGAAACCTGGCCCTGTCTTCTTGACGAGCATTCCTAGGGGTCTTTCCCC TCTCGCCAAAGGAATGCAAGGTCTGTTGAATGTCGTGAAGGAAGCAGTTCCTCTGGAAGCTTCTTGAAGA CAAACAACGTCTGTAGCGACCCTTTGCAGGCAGCGGAACCCCCCACCTGGCGACAGGTGCCTCTGCGGCC AAAAGCCACGTGTATAAGATACACCTGCAAAGGCGGCACAACCCCAGTGCCACGTTGTGAGTTGGATAGT TGTGGAAAGAGTCAAATGGCTCTCCTCAAGCGTATTCAACAAGGGGCTGAAGGATGCCCAGAAGGTACCC CATTGTATGGGATCTGATCTGGGGCCTCGGTGCACATGCTTTACATGTGTTTAGTCGAGGTTAAAAAAAC GTCTAGGCCCCCCGAACCACGGGGACGTGGTTTTCCTTTGAAAAACACGATAATAATATGTGCAGAAGGC CCGACTGCGGCTTCAGCTTCAGCCCTGGACCCGTGATCCTGCTGTGGTGCTGCCTGCTGCTGCCTATCGT GTCCTCTGCCGCCGTGTCTGTGGCCCCTACAGCCGCCGAGAAGGTGCCAGCCGAGTGCCCCGAGCTGACC AGAAGATGCCTGCTGGGCGAGGTGTTCGAGGGCGACAAGTACGAGAGCTGGCTGCGGCCCCTGGTCAACG TGACCGGCAGAGATGGCCCCCTGAGCCAGCTGATCCGGTACAGACCCGTGACCCCCGAGGCCGCCAATAG CGTGCTGCTGGACGAGGCCTTCCTGGATACCCTGGCCCTGCTGTACAACAACCCCGACCAGCTGAGAGCC CTGCTGACCCTGCTGTCCAGCGACACCGCCCCCAGATGGATGACC GTGATGCGGGGCTACAGCGAGTGTG GAGATGGCAGCCCTGCCGTGTACACCTGCGTGGACGACCTGTGCAGAGGCTACGACCTGACCAGACTGAG CTACGGCCGGTCCATCTTCACAGAGCACGTGCTGGGCTTCGAGCTGGTGCCCCCCAGCCTGTTCAACGTG GTGGTGGCCATCCGGAACGAGGCCACCAGAACCAACAGAGCCGTGCGGCTGCCTGTGTCTACAGCCGCTG CACCTGAGGGCATCACACTGTTCTACGGCCTGTACAACGCCGTGAAAGAGTTCTGCCTCCGGCACCAGCT GGATCCCCCCCTGCTGAGACACCTGGACAAGTACTACGCCGGCCTGCCCCCAGAGCTGAAGCAGACCAGA GTGAACCTGCCCGCCCACAGCAGATATGGCCCTCAGGCCGTGGACGCCAGATGATAAGCGGCCGCATACA GCAGCAATTGGCAAGCTGCTTACATAGAACTCGCGGCGATTGGCATGCCGCCTTAAAATTTTTATTTTAT TTTTCTTTTCTTTTCCGAATCGGATTTTGTTTTTAATATTTCAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAGGGTCGGCATGGCATCTCCACCTCCTCGCGGTCCGACCTGGGCATCCGAAGGAGGACGCACGT CCACTCGGATGGCTAAGGGAGAGCCACGTTTAAACACGTGATATCTGGCCTCATGGGCCTTCCTTTCACT GCCCGCTTTCCAGTCGGGAAACCTGTCGTGCCAGCTGCATTAACATGGTCATAGCTGTTTCCTTGCGTAT TGGGCGCTCTCCGCTTCCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGGTAAAGCCTGGGGTGCCTA ATGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTC CGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGA AACCCGACAGGACTATAAA GATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATA CCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCG GTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTAT CCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAA CAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTAC ACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCT CTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAG AAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCA CGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAA GTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTATTAGAAAAATTCATCCAGCAG ACGATAAAACGCAATACGCTGGCTATCCGGTGCCGCAATGCCATACAGCACCAGAAAACGATCCGCCCAT TCGCCGCCCAGTTCTTCCGCAATATCACGGGTGGCCAGCGCAATATCCTGATAACGATCCGCCACGCCCA GACGGCCGCAATCAATAAAGCCGCTAAAACGGCCATTTTCCACCATAATGTTCGGCAGGCACGCATCACC ATGGGTCACCACCAGATCTTCGCCATCCGGCATGCTCGCTTTCAGACGCGCAAACAG CTCTGCCGGTGCC AGGCCCTGATGTTCTTCATCCAGATCATCCTGATCCACCAGGCCCGCTTCCATACGGGTACGCGCACGTT CAATACGATGTTTCGCCTGATGATCAAACGGACAGGTCGCCGGGTCCAGGGTATGCAGACGACGCATGGC ATCCGCCATAATGCTCACTTTTTCTGCCGGCGCCAGATGGCTAGACAGCAGATCCTGACCCGGCACTTCG CCCAGCAGCAGCCAATCACGGCCCGCTTCGGTCACCACATCCAGCACCGCCGCACACGGAACACCGGTGG TGGCCAGCCAGCTCAGACGCGCCGCTTCATCCTGCAGCTCGTTCAGCGCACCGCTCAGATCGGTTTTCAC AAACAGCACCGGACGACCCTGCGCGCTCAGACGAAACACCGCCGCATCAGAGCAGCCAATGGTCTGCTGC GCCCAATCATAGCCAAACAGACGTTCCACCCACGCTGCCGGGCTACCCGCATGCAGGCCATCCTGTTCAA TCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATT TGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTAAATTG TAAGCGTTAATATTTTGTTAAAATTCGCGTTAAATTTTTGTTAAATCAGCTCATTTTTTAACCAATAGGC CGAAATCGGCAAAATCCCTTATAAATCAAAAGAATAGACCGAGATAGGGTTGAGTGGCCGCTACAGGGCG CTCCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGTTTCGGTGCGGGCCTCTTCGCTATTACG CCAGCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACAC GCGTAATACGACTCACTATAG Vector A537: SGP-342-EV71-gl-EMCV-gHsol ATAGGCGGCGCATGAGAGAAGCCCAGACCAATTACCTACCCAAAATGGAGAAAGTTCACGTTGACATCGA GGAAGACAGCCCATTCCTCAGAGCTTTGCAGCGGAGCTTCCCGCAGTTTGAGGTAGAAGCCAAGCAGGTC ACTGATAATGACCATGCTAATGCCAGAGCGTTTTCGCATCTGGCTTCAAAACTGATCGAAACGGAGGTGG ACCCATCCGACACGATCCTTGACATTGGAAGTGCGCCCGCCCGCAGAATGTATTCTAAGCACAAGTATCA TTGTATCTGTCCGATGAGATGTGCGGAAGATCCGGACAGATTGTATAAGTATGCAACTAAGCTGAAGAAA AACTGTAAGGAAATAACTGATAAGGAATTGGACAAGAAAATGAAGGAGCTCGCCGCCGTCATGAGCGACC CTGACCTGGAAACTGAGACTATGTGCCTCCACGACGACGAGTCGTGTCGCTACGAAGGGCAAGTCGCTGT TTACCAGGATGTATACGCGGTTGACGGACCGACAAGTCTCTATCACCAAGCCAATAAGGGAGTTAGAGTC GCCTACTGGATAGGCTTTGACACCACCCCTTTTATGTTTAAGAACTTGGCTGGAGCATATCCATCATACT CTACCAACTGGGCCGACGAAACCGTGTTAACGGCTCGTAACATAGGCCTATGCAGCTCTGACGTTATGGA GCGGTCACGTAGAGGGATGTCCATTCTTAGAAAGAAGTATTTGAAACCATCCAACAATGTTCTATTCTCT GTTGGCTCGACCATCTACCACGAGAAGAGGGACTTACTGAGGAGCTGGCACCTGCCGTCTGTATTTCACT TACGTGGCAAGCAAAATTACACATGTCGGTGTGAGACTATAGTTAGTTGCGACGGGTACGTCGTTAAAAG AATAGCTATCAGTCCAGGCCTGTATGGGAAGCCTTCAGGCTATGCTGCTA CGATGCACCGCGAGGGATTC TTGTGCTGCAAAGTGACAGACACATTGAACGGGGAGAGGGTCTCTTTTCCCGTGTGCACGTATGTGCCAG CTACATTGTGTGACCAAATGACTGGCATACTGGCAACAGATGTCAGTGCGGACGACGCGCAAAAACTGCT GGTTGGGCTCAACCAGCGTATAGTCGTCAACGGTCGCACCCAGAGAAACACCAATACCATGAAAAATTAC CTTTTGCCCGTAGTGGCCCAGGCATTTGCTAGGTGGGCAAAGGAATATAAGGAAGATCAAGAAGATGAAA GGCCACTAGGACTACGAGATAGACAGTTAGTCATGGGGTGTTGTTGGGCTTTTAGAAGGCACAAGATAAC ATCTATTTATAAGCGCCCGGATACCCAAACCATCATCAAAGTGAACAGCGATTTCCACTCATTCGTGCTG CCCAGGATAGGCAGTAACACATTGGAGATCGGGCTGAGAACAAGAATCAGGAAAATGTTAGAGGAGCACA AGGAGCCGTCACCTCTCATTACCGCCGAGGACGTACAAGAAGCTAAGTGCGCAGCCGATGAGGCTAAGGA GGTGCGTGAAGCCGAGGAGTTGCGCGCAGCTCTACCACCTTTGGCAGCTGATGTTGAGGAGCCCACTCTG GAAGCCGATGTCGACTTGATGTTACAAGAGGCTGGGGCCGGCTCAGTGGAGACACCTCGTGGCTTGATAA AGGTTACCAGCTACGATGGCGAGGACAAGATCGGCTCTTACGCTGTGCTTTCTCCGCAGGCTGTACTCAA GAGTGAAAAATTATCTTGCATCCACCCTCTCGCTGAACAAGTCATAGTGATAACACACTCTGGCCGAAAA GGGCGTTATGCCGTGGAACCATACCATGGTAAAGTAGTGGTGCCAGAGGGACATGCAATACCCGTCCAGG ACTTTCAAGCTCTGAGTGAAAGTGCCACCATTGTGTACAACGAACGTGAGTTCGTA AACAGGTACCTGCA CCATATTGCCACACATGGAGGAGCGCTGAACACTGATGAAGAATATTACAAAACTGTCAAGCCCAGCGAG CACGACGGCGAATACCTGTACGACATCGACAGGAAACAGTGCGTCAAGAAAGAACTAGTCACTGGGCTAG GGCTCACAGGCGAGCTGGTGGATCCTCCCTTCCATGAATTCGCCTACGAGAGTCTGAGAACACGACCAGC CGCTCCTTACCAAGTACCAACCATAGGGGTGTATGGCGTGCCAGGATCAGGCAAGTCTGGCATCATTAAA AGCGCAGTCACCAAAAAAGATCTAGTGGTGAGCGCCAAGAAAGAAAACTGTGCAGAAATTATAAGGGACG TCAAGAAAATGAAAGGGCTGGACGTCAATGCCAGAACTGTGGACTCAGTGCTCTTGAATGGATGCAAACA CCCCGTAGAGACCCTGTATATTGACGAAGCTTTTGCTTGTCATGCAGGTACTCTCAGAGCGCTCATAGCC ATTATAAGACCTAAAAAGGCAGTGCTCTGCGGGGATCCCAAACAGTGCGGTTTTTTTAACATGATGTGCC TGAAAGTGCATTTTAACCACGAGATTTGCACACAAGTCTTCCACAAAAGCATCTCTCGCCGTTGCACTAA ATCTGTGACTTCGGTCGTCTCAACCTTGTTTTACGACAAAAAAATGAGAACGACGAATCCGAAAGAGACT AAGATTGTGATTGACACTACCGGCAGTACCAAACCTAAGCAGGACGATCTCATTCTCACTTGTTTCAGAG GGTGGGTGAAGCAGTTGCAAATAGATTACAAAGGCAACGAAATAATGACGGCAGCTGCCTCTCAAGGGCT GACCCGTAAAGGTGTGTATGCCGTTCGGTACAAGGTGAATGAAAATCCTCTGTACGCACCCACCTCAGAA CATGTGAACGTCCTACTGACCCGCACGGAGGACCGCATCGTGTGGAAAACACTAGCCGGCGA CCCATGGA TAAAAACACTGACTGCCAAGTACCCTGGGAATTTCACTGCCACGATAGAGGAGTGGCAAGCAGAGCATGA TGCCATCATGAGGCACATCTTGGAGAGACCGGACCCTACCGACGTCTTCCAGAATAAGGCAAACGTGTGT TGGGCCAAGGCTTTAGTGCCGGTGCTGAAGACCGCTGGCATAGACATGACCACTGAACAATGGAACACTG TGGATTATTTTGAAACGGACAAAGCTCACTCAGCAGAGATAGTATTGAACCAACTATGCGTGAGGTTCTT TGGACTCGATCTGGACTCCGGTCTATTTTCTGCACCCACTGTTCCGTTATCCATTAGGAATAATCACTGG GATAACTCCCCGTCGCCTAACATGTACGGGCTGAATAAAGAAGTGGTCCGTCAGCTCTCTCGCAGGTACC CACAACTGCCTCGGGCAGTTGCCACTGGAAGAGTCTATGACATGAACACTGGTACACTGCGCAATTATGA TCCGCGCATAAACCTAGTACCTGTAAACAGAAGACTGCCTCATGCTTTAGTCCTCCACCATAATGAACAC CCACAGAGTGACTTTTCTTCATTCGTCAGCAAATTGAAGGGCAGAACTGTCCTGGTGGTCGGGGAAAAGT TGTCCGTCCCAGGCAAAATGGTTGACTGGTTGTCAGACCGGCCTGAGGCTACCTTCAGAGCTCGGCTGGA TTTAGGCATCCCAGGTGATGTGCCCAAATATGACATAATATTTGTTAATGTGAGGACCCCATATAAATAC CATCACTATCAGCAGTGTGAAGACCATGCCATTAAGCTTAGCATGTTGACCAAGAAAGCTTGTCTGCATC TGAATCCCGGCGGAACCTGTGTCAGCATAGGTTATGGTTACGCTGACAGGGCCAGCGAAAGCATCATTGG TGCTATAGCGCGGCAGTTCAAGTTTTCCCGGGTATGCAAACCGAAATCCTCACTTGAAGAGACGGAAG TT CTGTTTGTATTCATTGGGTACGATCGCAAGGCCCGTACGCACAATCCTTACAAGCTTTCATCAACCTTGA CCAACATTTATACAGGTTCCAGACTCCACGAAGCCGGATGTGCACCCTCATATCATGTGGTGCGAGGGGA TATTGCCACGGCCACCGAAGGAGTGATTATAAATGCTGCTAACAGCAAAGGACAACCTGGCGGAGGGGTG TGCGGAGCGCTGTATAAGAAATTCCCGGAAAGCTTCGATTTACAGCCGATCGAAGTAGGAAAAGCGCGAC TGGTCAAAGGTGCAGCTAAACATATCATTCATGCCGTAGGACCAAACTTCAACAAAGTTTCGGAGGTTGA AGGTGACAAACAGTTGGCAGAGGCTTATGAGTCCATCGCTAAGATTGTCAACGATAACAATTACAAGTCA GTAGCGATTCCACTGTTGTCCACCGGCATCTTTTCCGGGAACAAAGATCGACTAACCCAATCATTGAACC ATTTGCTGACAGCTTTAGACACCACTGATGCAGATGTAGCCATATACTGCAGGGACAAGAAATGGGAAAT GACTCTCAAGGAAGCAGTGGCTAGGAGAGAAGCAGTGGAGGAGATATGCATATCCGACGACTCTTCAGTG ACAGAACCTGATGCAGAGCTGGTGAGGGTGCATCCGAAGAGTTCTTTGGCTGGAAGGAAGGGCTACAGCA CAAGCGATGGCAAAACTTTCTCATATTTGGAAGGGACCAAGTTTCACCAGGCGGCCAAGGATATAGCAGA AATTAATGCCATGTGGCCCGTTGCAACGGAGGCCAATGAGCAGGTATGCATGTATATCCTCGGAGAAAGC ATGAGCAGTATTAGGTCGAAATGCCCCGTCGAAGAGTCGGAAGCCTCCACACCACCTAGCACGCTGCCTT TGT GCTTGTGCATCCATGCCATGACTCCAGAAAGAGTACAGCGCCTAAAAGCCTCACGTCCAGAACAAATTAC GTGCTCATCCTTTCCATTGCCGAAGTATAGAATCACTGGTGTGCAGAAGATCCAATGCTCCCAGCCT ATATTGTTCTCACCGAAAGTGCCTGCGTATATTCATCCAAGGAAGTATCTCGTGGAAACACCACCGGTAG ACGAGACTCCGGAGCCATCGGCAGAGAACCAATCCACAGAGGGGACACCTGAACAACCACCACTTATAAC CGAGGATGAGACCAGGACTAGAACGCCTGAGCCGATCATCATCGAAGAGGAAGAAGAGGATAGCATAAGT TTGCTGTCAGATGGCCCGACCCACCAGGTGCTGCAAGTCGAGGCAGACATTCACGGGCCGCCCTCTGTAT CTAGCTCATCCTGGTCCATTCCTCATGCATCCGACTTTGATGTGGACAGTTTATCCATACTTGACACCCT GGAGGGAGCTAGCGTGACCAGCGGGGCAACGTCAGCCGAGACTAACTCTTACTTCGCAAAGAGTATGGAG TTTCTGGCGCGACCGGTGCCTGCGCCTCGAACAGTATTCAGGAACCCTCCACATCCCGCTCCGCGCACAA GAACACCGTCACTTGCACCCAGCAGGGCCTGCTCGAGAACCAGCCTAGTTTCCACCCCGCCAGGCGTGAA TAGGGTGATCACTAGAGAGGAGCTCGAGGCGCTTACCCCGTCACGCACTCCTAGCAGGTCGGTCTCGAGA ACCAGCCTGGTCTCCAACCCGCCAGGCGTAAATAGGGTGATTACAAGAGAGGAGTTTGAGGCGTTCGTAG CACAACAACAATGACGGTTTGATGCGGGTGCATACATCTTTTCCTCCGACACCGGTCAAGGGCATTTACA ACAAAAATCAGTAAGGCAAACGGTGCTATCCGAAGTGGTGTTGGAGAGGACCGAATTGGAGATTTCGTAT GCCCCGCGCCTCGACCAAGAAAAAGAAGAATTACTACGCAAGAAATTACAGTTAAATCCCACACCTGCTA ACAGAAGCA GATACCAGTCCAGGAAGGTGGAGAACATGAAAGCCATAACAGCTAGACGTATTCTGCAAGG CCTAGGGCATTATTTGAAGGCAGAAGGAAAAGTGGAGTGCTACCGAACCCTGCATCCTGTTCCTTTGTAT TCATCTAGTGTGAACCGTGCCTTTTCAAGCCCCAAGGTCGCAGTGGAAGCCTGTAACGCCATGTTGAAAG AGAACTTTCCGACTGTGGCTTCTTACTGTATTATTCCAGAGTACGATGCCTATTTGGACATGGTTGACGG AGCTTCATGCTGCTTAGACACTGCCAGTTTTTGCCCTGCAAAGCTGCGCAGCTTTCCAAAGAAACACTCC TATTTGGAACCCACAATACGATCGGCAGTGCCTTCAGCGATCCAGAACACGCTCCAGAACGTCCTGGCAG CTGCCACAAAAAGAAATTGCAATGTCACGCAAATGAGAGAATTGCCCGTATTGGATTCGGCGGCCTTTAA TGTGGAATGCTTCAAGAAATATGCGTGTAATAATGAATATTGGGAAACGTTTAAAGAAAACCCCATCAGG CTTACTGAAGAAAACGTGGTAAATTACATTACCAAATTAAAAGGACCAAAAGCTGCTGCTCTTTTTGCGA AGACACATAATTTGAATATGTTGCAGGACATACCAATGGACAGGTTTGTAATGGACTTAAAGAGAGACGT GAAAGTGACTCCAGGAACAAAACATACTGAAGAACGGCCCAAGGTACAGGTGATCCAGGCTGCCGATCCG CTAGCAACAGCGTATCTGTGCGGAATCCACCGAGAGCTGGTTAGGAGATTAAATGCGGTCCTGCTTCCGA ACATTCATACACTGTTTGATATGTCGGCTGAAGACTTTGACGCTATTATAGCCGAGCACTTCCAGCCTGG GGATTGTGTTCTGGAAACTGACATCGCGTCGTTTGATAAAAGTGAGGACGACGCCATGGCTCTGACCGCG TTAATGATTCTGGAA GACTTAGGTGTGGACGCAGAGCTGTTGACGCTGATTGAGGCGGCTTTCGGCGAAA TTTCATCAATACATTTGCCCACTAAAACTAAATTTAAATTCGGAGCCATGATGAAATCTGGAATGTTCCT CACACTGTTTGTGAACACAGTCATTAACATTGTAATCGCAAGCAGAGTGTTGAGAGAACGGCTAACCGGA TCACCATGTGCAGCATTCATTGGAGATGACAATATCGTGAAAGGAGTCAAATCGGACAAATTAATGGCAG ACAGGTGCGCCACCTGGTTGAATATGGAAGTCAAGATTATAGATGCTGTGGTGGGCGAGAAAGCGCCTTA TTTCTGTGGAGGGTTTATTTTGTGTGACTCCGTGACCGGCACAGCGTGCCGTGTGGCAGACCCCCTAAAA AGGCTGTTTAAGCTTGGCAAACCTCTGGCAGCAGACGATGAACATGATGATGACAGGAGAAGGGCATTGC ATGAAGAGTCAACACGCTGGAACCGAGTGGGTATTCTTTCAGAGCTGTGCAAGGCAGTAGAATCAAGGTA TGAAACCGTAGGAACTTCCATCATAGTTATGGCCATGACTACTCTAGCTAGCAGTGTTAAATCATTCAGC TACCTGAGAGGGGCCCCTATAACTCTCTACGGCTAACCTGAATGGACTACGACATAGTCTAGTCCGCCAA GCTATTCCAGAAGTAGTGAGGAGGCTTTTTTGGAGGCCTAGGCTTTTGCAAAAAGCTTGTATATCCATTT TCGGATCTGATCAAGAGACAGGATGAGGATCGTTTCGCATGATTGAATAAGATGGATTGCACGTAGGTTC TCCGGCCGCTTGGGTGGAGAGGCTATTCGGCTATGACTGGGCACAACTGACAATCGGCTGCTCTGATGCC GCCGTGATCCGGTTGTCAGCGCAGGGGCGCCCGGTTCTTTTTGTCAAGACCGACCTGTCCGGTGCCCTGA ATGAACTGAAGGACGAGGCAG CGCGGCTATCGTGGCTGGCCACGACGGGCGTTCCTTGCGCAGTCTAGAC TGGCGCGCCAAACCTGCAGGTTAAAACAGCTGTGGGTTGTTCCCACCCACAGGGCCCACTGGGCGCTAGC ACTCTGATTTTACGAAATCCTTGTGCGCCTGTTTTATATCCCTTCCCTAATTCGAAACGTAGAAGCAATG CGCACCACTGATCAATAGTAGGCGTAACGCGCCAGTTACGTCATGATCAAGCATATCTGTTCCCCCGGAC TGAGTATCAATAGACTGCTTACGCGGTTGAAGGAGAAAACGTTCGTTATCCGGCTAACTACTTCGAGAAG CCCAGTAACACCATGGAAGCTGCAGGGTGTTTCGCTCAGCACTTCCCCCGTGTAGATCAGGTCGATGAGC CACTGCAATCCCCACAGGTGACTGTGGCAGTGGCTGCGTTGGCGGCCTGCCTATGGGGAGACCCATAGGA CGCTCTAATGTGGACATGGTGCGAAGAGCCTATTGAGCTAGTTAGTAGTCCTCCGGCCCCTGAATGCGGC TAATCCTAACTGCGGAGCACATGCCTTCAACCCAGAGGGTAGTGTGTCGTAATGGGCAACTCTGCAGCGG AACCGACTACTTTGGGTGTCCGTGTTTCTTTTTATTCTTATATTGGCTGCTTATGGTGACAATTACAGAA TTGTTACCATATAGCTATTGGATTGGCCATCCGGTGTGTAATAGAGCTGTTATATACCTATTTGTTGGCT TTGTACCACTAACTTTAAAATCTATAACTACCCTCAACTTTATATTAACCCTCAATACAGTTGAACATGT GCAGAAGGCCCGACTGCGGCTTCAGCTTCAGCCCTGGACCCGTGATCCTGCTGTGGTGCTGCCTGCTGCT GCCTATCGTGTCCTCTGCCGCCGTGTCTGTGGCCCCTACAGCCGCCGAGAAGGTGCCAGCCGAGTGCCCC GAGCTGACCAGAAGATGCCTGCTGGGC GAGGTGTTCGAGGGCGACAAGTACGAGAGCTGGCTGCGGCCCC TGGTCAACGTGACCGGCAGAGATGGCCCCCTGAGCCAGCTGATCCGGTACAGACCCGTGACCCCCGAGGC CGCCAATAGCGTGCTGCTGGACGAGGCCTTCCTGGATACCCTGGCCCTGCTGTACAACAACCCCGACCAG CTGAGAGCCCTGCTGACCCTGCTGTCCAGCGACACCGCCCCCAGATGGATGACCGTGATGCGGGGCTACA GCGAGTGTGGAGATGGCAGCCCTGCCGTGTACACCTGCGTGGACGACCTGTGCAGAGGCTACGACCTGAC CAGACTGAGCTACGGCCGGTCCATCTTCACAGAGCACGTGCTGGGCTTCGAGCTGGTGCCCCCCAGCCTG TTCAACGTGGTGGTGGCCATCCGGAACGAGGCCACCAGAACCAACAGAGCCGTGCGGCTGCCTGTGTCTA CAGCCGCTGCACCTGAGGGCATCACACTGTTCTACGGCCTGTACAACGCCGTGAAAGAGTTCTGCCTCCG GCACCAGCTGGATCCCCCCCTGCTGAGACACCTGGACAAGTACTACGCCGGCCTGCCCCCAGAGCTGAAG CAGACCAGAGTGAACCTGCCCGCCCACAGCAGATATGGCCCTCAGGCCGTGGACGCCAGATGATAACGCC GGCGCCCCCCCCTAACGTTACTGGCCGAAGCCGCTTGGAATAAGGCCGGTGTGCGTTTGTCTATATGTTA TTTTCCACCATATTGCCGTCTTTTGGCAATGTGAGGGCCCGGAAACCTGGCCCTGTCTTCTTGACGAGCA TTCCTAGGGGTCTTTCCCCTCTCGCCAAAGGAATGCAAGGTCTGTTGAATGTCGTGAAGGAAGCAGTTCC TCTGGAAGCTTCTTGAAGACAAACAACGTCTGTAGCGACCCTTTGCAGGCAGCGGAACCCCCCACCTGGC GACAGGTGCCTCTGCGGCCAAAAGCCACGTGTA TAAGATACACCTGCAAAGGCGGCACAACCCCAGTGCC ACGTTGTGAGTTGGATAGTTGTGGAAAGAGTCAAATGGCTCTCCTCAAGCGTATTCAACAAGGGGCTGAA GGATGCCCAGAAGGTACCCCATTGTATGGGATCTGATCTGGGGCCTCGGTGCACATGCTTTACATGTGTT TAGTCGAGGTTAAAAAAACGTCTAGGCCCCCCGAACCACGGGGACGTGGTTTTCCTTTGAAAAACACGAT AATAATATGAGGCCTGGCCTGCCCTCCTACCTGATCATCCTGGCCGTGTGCCTGTTCAGCCACCTGCTGT CCAGCAGATACGGCGCCGAGGCCGTGAGCGAGCCCCTGGACAAGGCTTTCCACCTGCTGCTGAACACCTA CGGCAGACCCATCCGGTTTCTGCGGGAGAACACCACCCAGTGCACCTACAACAGCAGCCTGCGGAACAGC ACCGTCGTGAGAGAGAACGCCATCAGCTTCAACTTTTTCCAGAGCTACAACCAGTACTACGTGTTCCACA TGCCCAGATGCCTGTTTGCCGGCCCTCTGGCCGAGCAGTTCCTGAACCAGGTGGACCTGACCGAGACACT GGAAAGATACCAGCAGCGGCTGAATACCTACGCCCTGGTGTCCAAGGACCTGGCCAGCTACCGGTCCTTT AGCCAGCAGCTCAAGGCTCAGGATAGCCTCGGCGAGCAGCCTACCACCGTGCCCCCTCCCATCGACCTGA GCATCCCCCACGTGTGGATGCCTCCCCAGACCACCCCTCACGGCTGGACCGAGAGCCACACCACCTCCGG CCTGCACAGACCCCACTTCAACCAGACCTGCATCCTGTTCGACGGCCACGACCTGCTGTTTAGCACCGTG ACCCCCTGCCTGCACCAGGGCTTCTACCTGATCGACGAGCTGAGATACGTGAAGATCACCCTGACCGAGG ATTTCTTCGTGGTCACCGTGTCCATCGACGACGACACCC CCATGCTGCTGATCTTCGGCCACCTGCCCAG AGTGCTGTTCAAGGCCCCCTACCAGCGGGACAACTTCATCCTGCGGCAGACCGAGAAGCACGAGCTGCTG GTGCTGGTCAAGAAGGACCAGCTGAACCGGCACTCCTACCTGAAGGACCCCGACTTCCTGGACGCCGCCC TGGACTTCAACTACCTGGACCTGAGCGCCCTGCTGAGAAACAGCTTCCACAGATACGCCGTGGACGTGCT GAAGTCCGGACGGTGCCAGATGCTCGATCGGCGGACCGTGGAGATGGCCTTCGCCTATGCCCTCGCCCTG TTCGCCGCTGCCAGACAGGAAGAGGCTGGCGCCCAGGTGTCAGTGCCCAGAGCCCTGGATAGACAGGCCG CCCTGCTGCAGATCCAGGAATTCATGATCACCTGCCTGAGCCAGACCCCCCCTAGAACCACCCTGCTGCT GTACCCCACAGCCGTGGATCTGGCCAAGAGGGCCCTGTGGACCCCCAACCAGATCACCGACATCACAAGC CTCGTGCGGCTCGTGTACATCCTGAGCAAGCAGAACCAGCAGCACCTGATCCCCCAGTGGGCCCTGAGAC AGATCGCCGACTTCGCCCTGAAGCTGCACAAGACCCATCTGGCCAGCTTTCTGAGCGCCTTCGCCAGGCA GGAACTGTACCTGATGGGCAGCCTGGTCCACAGCATGCTGGTGCATACCACCGAGCGGCGGGAGATCTTC ATCGTGGAGACAGGCCTGTGTAGCCTGGCCGAGCTGTCCCACTTTACCCAGCTGCTGGCCCACCCTCACC ACGAGTACCTGAGCGACCTGTACACCCCCTGCAGCAGCAGCGGCAGACGGGACCACAGCCTGGAACGGCT GACCAGACTGTTCCCCGATGCCACCGTGCCTGCTACAGTGCCTGCCGCCCTGTCCATCCTGTCCACCATG CAGCCCAGCACCCTGGAAACCTTCCCCGACCTGTTCTGCCTGCCC CTGGGCGAGAGCTTTAGCGCCCTGA CCGTGTCCGAGCACGTGTCCTACATCGTGACCAATCAGTACCTGATCAAGGGCATCAGCTACCCCGTGTC CACCACAGTCGTGGGCCAGAGCCTGATCATCACCCAGACCGACAGCCAGACCAAGTGCGAGCTGACCCGG AACATGCACACCACACACAGCATCACCGTGGCCCTGAACATCAGCCTGGAAAACTGCGCTTTCTGTCAGT CTGCCCTGCTGGAATACGACGATACCCAGGGCGTGATCAACATCATGTACATGCACGACAGCGACGACGT GCTGTTCGCCCTGGACCCCTACAACGAGGTGGTGGTGTCCAGCCCCCGGACCCACTACCTGATGCTGCTG AAGAACGGCACCGTGCTGGAAGTGACCGACGTGGTGGTGGACGCCACCGACTGATAAGCGGCCGCATACA GCAGCAATTGGCAAGCTGCTTACATAGAACTCGCGGCGATTGGCATGCCGCCTTAAAATTTTTATTTTAT TTTTCTTTTCTTTTCCGAATCGGATTTTGTTTTTAATATTTCAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAGGGTCGGCATGGCATCTCCACCTCCTCGCGGTCCGACCTGGGCATCCGAAGGAGGACGCACGT CCACTCGGATGGCTAAGGGAGAGCCACGTTTAAACACGTGATATCTGGCCTCATGGGCCTTCCTTTCACT GCCCGCTTTCCAGTCGGGAAACCTGTCGTGCCAGCTGCATTAACATGGTCATAGCTGTTTCCTTGCGTAT TGGGCGCTCTCCGCTTCCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGGTAAAGCCTGGGGTGCCTA ATGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTC CGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGA AACCCGACAGGACTATAAA GATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATA CCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCG GTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTAT CCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAA CAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTAC ACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCT CTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAG AAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCA CGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAA GTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTATTAGAAAAATTCATCCAGCAG ACGATAAAACGCAATACGCTGGCTATCCGGTGCCGCAATGCCATACAGCACCAGAAAACGATCCGCCCAT TCGCCGCCCAGTTCTTCCGCAATATCACGGGTGGCCAGCGCAATATCCTGATAACGATCCGCCACGCCCA GACGGCCGCAATCAATAAAGCCGCTAAAACGGCCATTTTCCACCATAATGTTCGGCAGGCACGCATCACC ATGGGTCACCACCAGATCTTCGCCATCCGGCATGCTCGCTTTCAGACGCGCAAACAG CTCTGCCGGTGCC AGGCCCTGATGTTCTTCATCCAGATCATCCTGATCCACCAGGCCCGCTTCCATACGGGTACGCGCACGTT CAATACGATGTTTCGCCTGATGATCAAACGGACAGGTCGCCGGGTCCAGGGTATGCAGACGACGCATGGC ATCCGCCATAATGCTCACTTTTTCTGCCGGCGCCAGATGGCTAGACAGCAGATCCTGACCCGGCACTTCG CCCAGCAGCAGCCAATCACGGCCCGCTTCGGTCACCACATCCAGCACCGCCGCACACGGAACACCGGTGG TGGCCAGCCAGCTCAGACGCGCCGCTTCATCCTGCAGCTCGTTCAGCGCACCGCTCAGATCGGTTTTCAC AAACAGCACCGGACGACCCTGCGCGCTCAGACGAAACACCGCCGCATCAGAGCAGCCAATGGTCTGCTGC GCCCAATCATAGCCAAACAGACGTTCCACCCACGCTGCCGGGCTACCCGCATGCAGGCCATCCTGTTCAA TCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATT TGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTAAATTG TAAGCGTTAATATTTTGTTAAAATTCGCGTTAAATTTTTGTTAAATCAGCTCATTTTTTAACCAATAGGC CGAAATCGGCAAAATCCCTTATAAATCAAAAGAATAGACCGAGATAGGGTTGAGTGGCCGCTACAGGGCG CTCCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGTTTCGGTGCGGGCCTCTTCGCTATTACG CCAGCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACAC GCGTAATACGACTCACTATAG Vector A554: SGP-SGP-gH-gL, UL128 SGP-SGP-SGP-UL130-UL131 ATAGGCGGCGCATGAGAGAAGCCCAGACCAATTACCTACCCAAAATGGAGAAAGTTCACGTTGACATCGA GGAAGACAGCCCATTCCTCAGAGCTTTGCAGCGGAGCTTCCCGCAGTTTGAGGTAGAAGCCAAGCAGGTC ACTGATAATGACCATGCTAATGCCAGAGCGTTTTCGCATCTGGCTTCAAAACTGATCGAAACGGAGGTGG ACCCATCCGACACGATCCTTGACATTGGAAGTGCGCCCGCCCGCAGAATGTATTCTAAGCACAAGTATCA TTGTATCTGTCCGATGAGATGTGCGGAAGATCCGGACAGATTGTATAAGTATGCAACTAAGCTGAAGAAA AACTGTAAGGAAATAACTGATAAGGAATTGGACAAGAAAATGAAGGAGCTCGCCGCCGTCATGAGCGACC CTGACCTGGAAACTGAGACTATGTGCCTCCACGACGACGAGTCGTGTCGCTACGAAGGGCAAGTCGCTGT TTACCAGGATGTATACGCGGTTGACGGACCGACAAGTCTCTATCACCAAGCCAATAAGGGAGTTAGAGTC GCCTACTGGATAGGCTTTGACACCACCCCTTTTATGTTTAAGAACTTGGCTGGAGCATATCCATCATACT CTACCAACTGGGCCGACGAAACCGTGTTAACGGCTCGTAACATAGGCCTATGCAGCTCTGACGTTATGGA GCGGTCACGTAGAGGGATGTCCATTCTTAGAAAGAAGTATTTGAAACCATCCAACAATGTTCTATTCTCT GTTGGCTCGACCATCTACCACGAGAAGAGGGACTTACTGAGGAGCTGGCACCTGCCGTCTGTATTTCACT TACGTGGCAAGCAAAATTACACATGTCGGTGTGAGACTATAGTTAGTTGCGACGGGTACGTCGTTAAAAG AATAGCTATCAGTCCAGGCCTGTATGGGAAGCC TTCAGGCTATGCTGCTACGATGCACCGCGAGGGATTC TTGTGCTGCAAAGTGACAGACACATTGAACGGGGAGAGGGTCTCTTTTCCCGTGTGCACGTATGTGCCAG CTACATTGTGTGACCAAATGACTGGCATACTGGCAACAGATGTCAGTGCGGACGACGCGCAAAAACTGCT GGTTGGGCTCAACCAGCGTATAGTCGTCAACGGTCGCACCCAGAGAAACACCAATACCATGAAAAATTAC CTTTTGCCCGTAGTGGCCCAGGCATTTGCTAGGTGGGCAAAGGAATATAAGGAAGATCAAGAAGATGAAA GGCCACTAGGACTACGAGATAGACAGTTAGTCATGGGGTGTTGTTGGGCTTTTAGAAGGCACAAGATAAC ATCTATTTATAAGCGCCCGGATACCCAAACCATCATCAAAGTGAACAGCGATTTCCACTCATTCGTGCTG CCCAGGATAGGCAGTAACACATTGGAGATCGGGCTGAGAACAAGAATCAGGAAAATGTTAGAGGAGCACA AGGAGCCGTCACCTCTCATTACCGCCGAGGACGTACAAGAAGCTAAGTGCGCAGCCGATGAGGCTAAGGA GGTGCGTGAAGCCGAGGAGTTGCGCGCAGCTCTACCACCTTTGGCAGCTGATGTTGAGGAGCCCACTCTG GAAGCCGATGTAGACTTGATGTTACAAGAGGCTGGGGCCGGCTCAGTGGAGACACCTCGTGGCTTGATAA AGGTTACCAGCTACGATGGCGAGGACAAGATCGGCTCTTACGCTGTGCTTTCTCCGCAGGCTGTACTCAA GAGTGAAAAATTATCTTGCATCCACCCTCTCGCTGAACAAGTCATAGTGATAACACACTCTGGCCGAAAA GGGCGTTATGCCGTGGAACCATACCATGGTAAAGTAGTGGTGCCAGAGGGACATGCAATACCCGTCCAGG ACTTTCAAGCTCTGAGTGAAAGTGCCACCATTGTGTACA ACGAACGTGAGTTCGTAAACAGGTACCTGCA CCATATTGCCACACATGGAGGAGCGCTGAACACTGATGAAGAATATTACAAAACTGTCAAGCCCAGCGAG CACGACGGCGAATACCTGTACGACATCGACAGGAAACAGTGCGTCAAGAAAGAACTAGTCACTGGGCTAG GGCTCACAGGCGAGCTGGTGGATCCTCCCTTCCATGAATTCGCCTACGAGAGTCTGAGAACACGACCAGC CGCTCCTTACCAAGTACCAACCATAGGGGTGTATGGCGTGCCAGGATCAGGCAAGTCTGGCATCATTAAA AGCGCAGTCACCAAAAAAGATCTAGTGGTGAGCGCCAAGAAAGAAAACTGTGCAGAAATTATAAGGGACG TCAAGAAAATGAAAGGGCTGGACGTCAATGCCAGAACTGTGGACTCAGTGCTCTTGAATGGATGCAAACA CCCCGTAGAGACCCTGTATATTGACGAAGCTTTTGCTTGTCATGCAGGTACTCTCAGAGCGCTCATAGCC ATTATAAGACCTAAAAAGGCAGTGCTCTGCGGGGATCCCAAACAGTGCGGTTTTTTTAACATGATGTGCC TGAAAGTGCATTTTAACCACGAGATTTGCACACAAGTCTTCCACAAAAGCATCTCTCGCCGTTGCACTAA ATCTGTGACTTCGGTCGTCTCAACCTTGTTTTACGACAAAAAAATGAGAACGACGAATCCGAAAGAGACT AAGATTGTGATTGACACTACCGGCAGTACCAAACCTAAGCAGGACGATCTCATTCTCACTTGTTTCAGAG GGTGGGTGAAGCAGTTGCAAATAGATTACAAAGGCAACGAAATAATGACGGCAGCTGCCTCTCAAGGGCT GACCCGTAAAGGTGTGTATGCCGTTCGGTACAAGGTGAATGAAAATCCTCTGTACGCACCCACCTCAGAA CATGTGAACGTCCTACTGACCCGCACGGAGGACCGCATCGTGTGG AAAACACTAGCCGGCGACCCATGGA TAAAAACACTGACTGCCAAGTACCCTGGGAATTTCACTGCCACGATAGAGGAGTGGCAAGCAGAGCATGA TGCCATCATGAGGCACATCTTGGAGAGACCGGACCCTACCGACGTCTTCCAGAATAAGGCAAACGTGTGT TGGGCCAAGGCTTTAGTGCCGGTGCTGAAGACCGCTGGCATAGACATGACCACTGAACAATGGAACACTG TGGATTATTTTGAAACGGACAAAGCTCACTCAGCAGAGATAGTATTGAACCAACTATGCGTGAGGTTCTT TGGACTCGATCTGGACTCCGGTCTATTTTCTGCACCCACTGTTCCGTTATCCATTAGGAATAATCACTGG GATAACTCCCCGTCGCCTAACATGTACGGGCTGAATAAAGAAGTGGTCCGTCAGCTCTCTCGCAGGTACC CACAACTGCCTCGGGCAGTTGCCACTGGAAGAGTCTATGACATGAACACTGGTACACTGCGCAATTATGA TCCGCGCATAAACCTAGTACCTGTAAACAGAAGACTGCCTCATGCTTTAGTCCTCCACCATAATGAACAC CCACAGAGTGACTTTTCTTCATTCGTCAGCAAATTGAAGGGCAGAACTGTCCTGGTGGTCGGGGAAAAGT TGTCCGTCCCAGGCAAAATGGTTGACTGGTTGTCAGACCGGCCTGAGGCTACCTTCAGAGCTCGGCTGGA TTTAGGCATCCCAGGTGATGTGCCCAAATATGACATAATATTTGTTAATGTGAGGACCCCATATAAATAC CATCACTATCAGCAGTGTGAAGACCATGCCATTAAGCTTAGCATGTTGACCAAGAAAGCTTGTCTGCATC TGAATCCCGGCGGAACCTGTGTCAGCATAGGTTATGGTTACGCTGACAGGGCCAGCGAAAGCATCATTGG TGCTATAGCGCGGCAGTTCAAGTTTTCCCGGGTATGCAAACCGAAATCCTC ACTTGAAGAGACGGAAGTT CTGTTTGTATTCATTGGGTACGATCGCAAGGCCCGTACGCACAATCCTTACAAGCTTTCATCAACCTTGA CCAACATTTATACAGGTTCCAGACTCCACGAAGCCGGATGTGCACCCTCATATCATGTGGTGCGAGGGGA TATTGCCACGGCCACCGAAGGAGTGATTATAAATGCTGCTAACAGCAAAGGACAACCTGGCGGAGGGGTG TGCGGAGCGCTGTATAAGAAATTCCCGGAAAGCTTCGATTTACAGCCGATCGAAGTAGGAAAAGCGCGAC TGGTCAAAGGTGCAGCTAAACATATCATTCATGCCGTAGGACCAAACTTCAACAAAGTTTCGGAGGTTGA AGGTGACAAACAGTTGGCAGAGGCTTATGAGTCCATCGCTAAGATTGTCAACGATAACAATTACAAGTCA GTAGCGATTCCACTGTTGTCCACCGGCATCTTTTCCGGGAACAAAGATCGACTAACCCAATCATTGAACC ATTTGCTGACAGCTTTAGACACCACTGATGCAGATGTAGCCATATACTGCAGGGACAAGAAATGGGAAAT GACTCTCAAGGAAGCAGTGGCTAGGAGAGAAGCAGTGGAGGAGATATGCATATCCGACGACTCTTCAGTG ACAGAACCTGATGCAGAGCTGGTGAGGGTGCATCCGAAGAGTTCTTTGGCTGGAAGGAAGGGCTACAGCA CAAGCGATGGCAAAACTTTCTCATATTTGGAAGGGACCAAGTTTCACCAGGCGGCCAAGGATATAGCAGA AATTAATGCCATGTGGCCCGTTGCAACGGAGGCCAATGAGCAGGTATGCATGTATATCCTCGGAGAAAGC ATGAGCAGTATTAGGTCGAAATGCCCCGTCGAAGAGTCGGAAGCCTCCACACCACCTAGCACGCTGCCTT GCTTGTGCATCCATGCCATGACTCCAGAAAGAGTACAGCGCCTAAAAGCCTCACGTC CAGAACAAATTAC TGTGTGCTCATCCTTTCCATTGCCGAAGTATAGAATCACTGGTGTGCAGAAGATCCAATGCTCCCAGCCT ATATTGTTCTCACCGAAAGTGCCTGCGTATATTCATCCAAGGAAGTATCTCGTGGAAACACCACCGGTAG ACGAGACTCCGGAGCCATCGGCAGAGAACCAATCCACAGAGGGGACACCTGAACAACCACCACTTATAAC CGAGGATGAGACCAGGACTAGAACGCCTGAGCCGATCATCATCGAAGAGGAAGAAGAGGATAGCATAAGT TTGCTGTCAGATGGCCCGACCCACCAGGTGCTGCAAGTCGAGGCAGACATTCACGGGCCGCCCTCTGTAT CTAGCTCATCCTGGTCCATTCCTCATGCATCCGACTTTGATGTGGACAGTTTATCCATACTTGACACCCT GGAGGGAGCTAGCGTGACCAGCGGGGCAACGTCAGCCGAGACTAACTCTTACTTCGCAAAGAGTATGGAG TTTCTGGCGCGACCGGTGCCTGCGCCTCGAACAGTATTCAGGAACCCTCCACATCCCGCTCCGCGCACAA GAACACCGTCACTTGCACCCAGCAGGGCCTGCTCGAGAACCAGCCTAGTTTCCACCCCGCCAGGCGTGAA TAGGGTGATCACTAGAGAGGAGCTCGAGGCGCTTACCCCGTCACGCACTCCTAGCAGGTCGGTCTCGAGA ACCAGCCTGGTCTCCAACCCGCCAGGCGTAAATAGGGTGATTACAAGAGAGGAGTTTGAGGCGTTCGTAG CACAACAACAATGACGGTTTGATGCGGGTGCATACATCTTTTCCTCCGACACCGGTCAAGGGCATTTACA ACAAAAATCAGTAAGGCAAACGGTGCTATCCGAAGTGGTGTTGGAGAGGACCGAATTGGAGATTTCGTAT GCCCCGCGCCTCGACCAAGAAAAAGAAGAATTACTACGCAAGAAATTACAGTTAAATCCCACA CCTGCTA ACAGAAGCAGATACCAGTCCAGGAAGGTGGAGAACATGAAAGCCATAACAGCTAGACGTATTCTGCAAGG CCTAGGGCATTATTTGAAGGCAGAAGGAAAAGTGGAGTGCTACCGAACCCTGCATCCTGTTCCTTTGTAT TCATCTAGTGTGAACCGTGCCTTTTCAAGCCCCAAGGTCGCAGTGGAAGCCTGTAACGCCATGTTGAAAG AGAACTTTCCGACTGTGGCTTCTTACTGTATTATTCCAGAGTACGATGCCTATTTGGACATGGTTGACGG AGCTTCATGCTGCTTAGACACTGCCAGTTTTTGCCCTGCAAAGCTGCGCAGCTTTCCAAAGAAACACTCC TATTTGGAACCCACAATACGATCGGCAGTGCCTTCAGCGATCCAGAACACGCTCCAGAACGTCCTGGCAG CTGCCACAAAAAGAAATTGCAATGTCACGCAAATGAGAGAATTGCCCGTATTGGATTCGGCGGCCTTTAA TGTGGAATGCTTCAAGAAATATGCGTGTAATAATGAATATTGGGAAACGTTTAAAGAAAACCCCATCAGG CTTACTGAAGAAAACGTGGTAAATTACATTACCAAATTAAAAGGACCAAAAGCTGCTGCTCTTTTTGCGA AGACACATAATTTGAATATGTTGCAGGACATACCAATGGACAGGTTTGTAATGGACTTAAAGAGAGACGT GAAAGTGACTCCAGGAACAAAACATACTGAAGAACGGCCCAAGGTACAGGTGATCCAGGCTGCCGATCCG CTAGCAACAGCGTATCTGTGCGGAATCCACCGAGAGCTGGTTAGGAGATTAAATGCGGTCCTGCTTCCGA ACATTCATACACTGTTTGATATGTCGGCTGAAGACTTTGACGCTATTATAGCCGAGCACTTCCAGCCTGG GGATTGTGTTCTGGAAACTGACATCGCGTCGTTTGATAAAAGTGAGGACGACGCCATGGCTCTGACCGC G TTAATGATTCTGGAAGACTTAGGTGTGGACGCAGAGCTGTTGACGCTGATTGAGGCGGCTTTCGGCGAAA TTTCATCAATACATTTGCCCACTAAAACTAAATTTAAATTCGGAGCCATGATGAAATCTGGAATGTTCCT CACACTGTTTGTGAACACAGTCATTAACATTGTAATCGCAAGCAGAGTGTTGAGAGAACGGCTAACCGGA TCACCATGTGCAGCATTCATTGGAGATGACAATATCGTGAAAGGAGTCAAATCGGACAAATTAATGGCAG ACAGGTGCGCCACCTGGTTGAATATGGAAGTCAAGATTATAGATGCTGTGGTGGGCGAGAAAGCGCCTTA TTTCTGTGGAGGGTTTATTTTGTGTGACTCCGTGACCGGCACAGCGTGCCGTGTGGCAGACCCCCTAAAA AGGCTGTTTAAGCTTGGCAAACCTCTGGCAGCAGACGATGAACATGATGATGACAGGAGAAGGGCATTGC ATGAAGAGTCAACACGCTGGAACCGAGTGGGTATTCTTTCAGAGCTGTGCAAGGCAGTAGAATCAAGGTA TGAAACCGTAGGAACTTCCATCATAGTTATGGCCATGACTACTCTAGCTAGCAGTGTTAAATCATTCAGC TACCTGAGAGGGGCCCCTATAACTCTCTACGGCTAACCTGAATGGACTACGACATAGTCTAGTCCGCCAA GATGAGGCCTGGCCTGCCCTCCTACCTGATCATCCTGGCCGTGTGCCTGTTCAGCCACCTGCTGTCCAGC AGATACGGCGCCGAGGCCGTGAGCGAGCCCCTGGACAAGGCTTTCCACCTGCTGCTGAACACCTACGGCA GACCCATCCGGTTTCTGCGGGAGAACACCACCCAGTGCACCTACAACAGCAGCCTGCGGAACAGCACCGT CGTGAGAGAGAACGCCATCAGCTTCAACTTTTTCCAGAGCTACAACCAGTACTACGTGTTCCACATGCCC AGAT GCCTGTTTGCCGGCCCTCTGGCCGAGCAGTTCCTGAACCAGGTGGACCTGACCGAGACACTGGAAA GATACCAGCAGCGGCTGAATACCTACGCCCTGGTGTCCAAGGACCTGGCCAGCTACCGGTCCTTTAGCCA GCAGCTCAAGGCTCAGGATAGCCTCGGCGAGCAGCCTACCACCGTGCCCCCTCCCATCGACCTGAGCATC CCCCACGTGTGGATGCCTCCCCAGACCACCCCTCACGGCTGGACCGAGAGCCACACCACCTCCGGCCTGC ACAGACCCCACTTCAACCAGACCTGCATCCTGTTCGACGGCCACGACCTGCTGTTTAGCACCGTGACCCC CTGCCTGCACCAGGGCTTCTACCTGATCGACGAGCTGAGATACGTGAAGATCACCCTGACCGAGGATTTC TTCGTGGTCACCGTGTCCATCGACGACGACACCCCCATGCTGCTGATCTTCGGCCACCTGCCCAGAGTGC TGTTCAAGGCCCCCTACCAGCGGGACAACTTCATCCTGCGGCAGACCGAGAAGCACGAGCTGCTGGTGCT GGTCAAGAAGGACCAGCTGAACCGGCACTCCTACCTGAAGGACCCCGACTTCCTGGACGCCGCCCTGGAC TTCAACTACCTGGACCTGAGCGCCCTGCTGAGAAACAGCTTCCACAGATACGCCGTGGACGTGCTGAAGT CCGGACGGTGCCAGATGCTCGATCGGCGGACCGTGGAGATGGCCTTCGCCTATGCCCTCGCCCTGTTCGC CGCTGCCAGACAGGAAGAGGCTGGCGCCCAGGTGTCAGTGCCCAGAGCCCTGGATAGACAGGCCGCCCTG CTGCAGATCCAGGAATTCATGATCACCTGCCTGAGCCAGACCCCCCCTAGAACCACCCTGCTGCTGTACC CCACAGCCGTGGATCTGGCCAAGAGGGCCCTGTGGACCCCCAACCAGATCACCGACATCACAAGCCTCGT GCGGCTCGTG TACATCCTGAGCAAGCAGAACCAGCAGCACCTGATCCCCCAGTGGGCCCTGAGACAGATC GCCGACTTCGCCCTGAAGCTGCACAAGACCCATCTGGCCAGCTTTCTGAGCGCCTTCGCCAGGCAGGAAC TGTACCTGATGGGCAGCCTGGTCCACAGCATGCTGGTGCATACCACCGAGCGGCGGGAGATCTTCATCGT GGAGACAGGCCTGTGTAGCCTGGCCGAGCTGTCCCACTTTACCCAGCTGCTGGCCCACCCTCACCACGAG TACCTGAGCGACCTGTACACCCCCTGCAGCAGCAGCGGCAGACGGGACCACAGCCTGGAACGGCTGACCA GACTGTTCCCCGATGCCACCGTGCCTGCTACAGTGCCTGCCGCCCTGTCCATCCTGTCCACCATGCAGCC CAGCACCCTGGAAACCTTCCCCGACCTGTTCTGCCTGCCCCTGGGCGAGAGCTTTAGCGCCCTGACCGTG TCCGAGCACGTGTCCTACATCGTGACCAATCAGTACCTGATCAAGGGCATCAGCTACCCCGTGTCCACCA CAGTCGTGGGCCAGAGCCTGATCATCACCCAGACCGACAGCCAGACCAAGTGCGAGCTGACCCGGAACAT GCACACCACACACAGCATCACCGTGGCCCTGAACATCAGCCTGGAAAACTGCGCTTTCTGTCAGTCTGCC CTGCTGGAATACGACGATACCCAGGGCGTGATCAACATCATGTACATGCACGACAGCGACGACGTGCTGT TCGCCCTGGACCCCTACAACGAGGTGGTGGTGTCCAGCCCCCGGACCCACTACCTGATGCTGCTGAAGAA CGGCACCGTGCTGGAAGTGACCGACGTGGTGGTGGACGCCACCGACAGCAGACTGCTGATGATGAGCGTG TACGCCCTGAGCGCCATCATCGGCATCTACCTGCTGTACCGGATGCTGAAAACCTGCTGATAATCTAGAG GCCCCTATAACTCTCT ACGGCTAACCTGAATGGACTACGACATAGTCTAGTCCGCCAAGATGTGCAGAAG GCCCGACTGCGGCTTCAGCTTCAGCCCTGGACCCGTGATCCTGCTGTGGTGCTGCCTGCTGCTGCCTATC GTGTCCTCTGCCGCCGTGTCTGTGGCCCCTACAGCCGCCGAGAAGGTGCCAGCCGAGTGCCCCGAGCTGA CCAGAAGATGCCTGCTGGGCGAGGTGTTCGAGGGCGACAAGTACGAGAGCTGGCTGCGGCCCCTGGTCAA CGTGACCGGCAGAGATGGCCCCCTGAGCCAGCTGATCCGGTACAGACCCGTGACCCCCGAGGCCGCCAAT AGCGTGCTGCTGGACGAGGCCTTCCTGGATACCCTGGCCCTGCTGTACAACAACCCCGACCAGCTGAGAG CCCTGCTGACCCTGCTGTCCAGCGACACCGCCCCCAGATGGATGACCGTGATGCGGGGCTACAGCGAGTG TGGAGATGGCAGCCCTGCCGTGTACACCTGCGTGGACGACCTGTGCAGAGGCTACGACCTGACCAGACTG AGCTACGGCCGGTCCATCTTCACAGAGCACGTGCTGGGCTTCGAGCTGGTGCCCCCCAGCCTGTTCAACG TGGTGGTGGCCATCCGGAACGAGGCCACCAGAACCAACAGAGCCGTGCGGCTGCCTGTGTCTACAGCCGC TGCACCTGAGGGCATCACACTGTTCTACGGCCTGTACAACGCCGTGAAAGAGTTCTGCCTCCGGCACCAG CTGGATCCCCCCCTGCTGAGACACCTGGACAAGTACTACGCCGGCCTGCCCCCAGAGCTGAAGCAGACCA GAGTGAACCTGCCCGCCCACAGCAGATATGGCCCTCAGGCCGTGGACGCCAGATGATAACGCCGGCGGCC CCTATAACTCTCTACGGCTAACCTGAATGGACTACGACATAGTCTAGTCCGCCAAGATGAGCCCCAAGGA CCTGACCCCCTTCCTGACAACC CTGTGGCTGCTCCTGGGCCATAGCAGAGTGCCTAGAGTGCGGGCCGAG GAATGCTGCGAGTTCATCAACGTGAACCACCCCCCCGAGCGGTGCTACGACTTCAAGATGTGCAACCGGT TCACCGTGGCCCTGAGATGCCCCGACGGCGAAGTGTGCTACAGCCCCGAGAAAACCGCCGAGATCCGGGG CATCGTGACCACCATGACCCACAGCCTGACCCGGCAGGTGGTGCACAACAAGCTGACCAGCTGCAACTAC AACCCCCTGTACCTGGAAGCCGACGGCCGGATCAGATGCGGCAAAGTGAACGACAAGGCCCAGTACCTGC TGGGAGCCGCCGGAAGCGTGCCCTACCGGTGGATCAACCTGGAATACGACAAGATCACCCGGATCGTGGG CCTGGACCAGTACCTGGAAAGCGTGAAGAAGCACAAGCGGCTGGACGTGTGCAGAGCCAAGATGGGCTAC ATGCTGCAGTGATAAGGCGCGCCGCCCCTATAACTCTCTACGGCTAACCTGAATGGACTACGACATAGTC TAGTCCGCCAAGATGCTGCGGCTGCTGCTGAGACACCACTTCCACTGCCTGCTGCTGTGTGCCGTGTGGG CCACCCCTTGTCTGGCCAGCCCTTGGAGCACCCTGACCGCCAACCAGAACCCTAGCCCCCCTTGGTCCAA GCTGACCTACAGCAAGCCCCACGACGCCGCCACCTTCTACTGCCCCTTTCTGTACCCCAGCCCTCCCAGA AGCCCCCTGCAGTTCAGCGGCTTCCAGAGAGTGTCCACCGGCCCTGAGTGCCGGAACGAGACACTGTACC TGCTGTACAACCGGGAGGGCCAGACACTGGTGGAGCGGAGCAGCACCTGGGTGAAAAAAGTGATCTGGTA TCTGAGCGGCCGGAACCAGACCATCCTGCAGCGGATGCCCAGAACCGCCAGCAAGCCCAGCGACGGCAAC GTGCAGATCAGCGTGGAGGACGCCAAAA TCTTCGGAGCCCACATGGTGCCCAAGCAGACCAAGCTGCTGA GATTCGTGGTCAACGACGGCACCAGATATCAGATGTGCGTGATGAAGCTGGAAAGCTGGGCCCACGTGTT CCGGGACTACTCCGTGAGCTTCCAGGTCCGGCTGACCTTCACCGAGGCCAACAACCAGACCTACACCTTC TGCACCCACCCCAACCTGATCGTGTGATAAGCGGCCGCGCCCCTATAACTCTCTACGGCTAACCTGAATG GACTACGACATAGTCTAGTCCGCCAAGATGCGGCTGTGCAGAGTGTGGCTGTCCGTGTGCCTGTGTGCCG TGGTGCTGGGCCAGTGCCAGAGAGAGACAGCCGAGAAGAACGACTACTACCGGGTGCCCCACTACTGGGA TGCCTGCAGCAGAGCCCTGCCCGACCAGACCCGGTACAAATACGTGGAGCAGCTCGTGGACCTGACCCTG AACTACCACTACGACGCCAGCCACGGCCTGGACAACTTCGACGTGCTGAAGCGGATCAACGTGACCGAGG TGTCCCTGCTGATCAGCGACTTCCGGCGGCAGAACAGAAGAGGCGGCACCAACAAGCGGACCACCTTCAA CGCCGCTGGCTCTCTGGCCCCTCACGCCAGATCCCTGGAATTCAGCGTGCGGCTGTTCGCCAACTGATAA CGTTGCATCCTGCAGGATACAGCAGCAATTGGCAAGCTGCTTACATAGAACTCGCGGCGATTGGCATGCC GCCTTAAAATTTTTATTTTATTTTTCTTTTCTTTTCCGAATCGGATTTTGTTTTTAATATTTCAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAGGGTCGGCATGGCATCTCCACCTCCTCGCGGTCCGACCTGGG CATCCGAAGGAGGACGCACGTCCACTCGGATGGCTAAGGGAGAGCCACGTTTAAACGCTAGAGCAAGACG TTTCCCGTTGAATATGGCTCATAACACCCCTTGT ATTACTGTTTATGTAAGCAGACAGTTTTATTGTTCA TGATGATATATTTTTATCTTGTGCAATGTAACATCAGAGATTTTGAGACACAACGTGGCTTTGTTGAATA AATCGAACTTTTGCTGAGTTGAAGGATCAGATCACGCATCTTCCCGACAACGCAGACCGTTCCGTGGCAA AGCAAAAGTTCAAAATCACCAACTGGTCCACCTACAACAAAGCTCTCATCAACCGTGGCTCCCTCACTTT CTGGCTGGATGATGGGGCGATTCAGGCCTGGTATGAGTCAGCAACACCTTCTTCACGAGGCAGACCTCAG CGCTAGCGGAGTGTATACTGGCTTACTATGTTGGCACTGATGAGGGTGTCAGTGAAGTGCTTCATGTGGC AGGAGAAAAAAGGCTGCACCGGTGCGTCAGCAGAATATGTGATACAGGATATATTCCGCTTCCTCGCTCA CTGACTCGCTACGCTCGGTCGTTCGACTGCGGCGAGCGGAAATGGCTTACGAACGGGGCGGAGATTTCCT GGAAGATGCCAGGAAGATACTTAACAGGGAAGTGAGAGGGCCGCGGCAAAGCCGTTTTTCCATAGGCTCC GCCCCCCTGACAAGCATCACGAAATCTGACGCTCAAATCAGTGGTGGCGAAACCCGACAGGACTATAAAG ATACCAGGCGTTTCCCCTGGCGGCTCCCTCGTGCGCTCTCCTGTTCCTGCCTTTCGGTTTACCGGTGTCA TTCCGCTGTTATGGCCGCGTTTGTCTCATTCCACGCCTGACACTCAGTTCCGGGTAGGCAGTTCGCTCCA AGCTGGACTGTATGCACGAACCCCCCGTTCAGTCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGA GTCCAACCCGGAAAGACATGCAAAAGCACCACTGGCAGCAGCCACTGGTAATTGATTTAGAGGAGTTAGT CTTGAAGTCATGCGCCGGTTAAGGCTAAACTGAAAGGACA AGTTTTGGTGACTGCGCTCCTCCAAGCCAG TTACCTCGGTTCAAAGAGTTGGTAGCTCAGAGAACCTTCGAAAAACCGCCCTGCAAGGCGGTTTTTTCGT TTTCAGAGCAAGAGATTACGCGCAGACCAAAACGATCTCAAGAAGATCATCTTATTAAGGGGTCTGACGC TCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATC CTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTATT AGAAAAATTCATCCAGCAGACGATAAAACGCAATACGCTGGCTATCCGGTGCCGCAATGCCATACAGCAC CAGAAAACGATCCGCCCATTCGCCGCCCAGTTCTTCCGCAATATCACGGGTGGCCAGCGCAATATCCTGA TAACGATCCGCCACGCCCAGACGGCCGCAATCAATAAAGCCGCTAAAACGGCCATTTTCCACCATAATGT TCGGCAGGCACGCATCACCATGGGTCACCACCAGATCTTCGCCATCCGGCATGCTCGCTTTCAGACGCGC AAACAGCTCTGCCGGTGCCAGGCCCTGATGTTCTTCATCCAGATCATCCTGATCCACCAGGCCCGCTTCC ATACGGGTACGCGCACGTTCAATACGATGTTTCGCCTGATGATCAAACGGACAGGTCGCCGGGTCCAGGG TATGCAGACGACGCATGGCATCCGCCATAATGCTCACTTTTTCTGCCGGCGCCAGATGGCTAGACAGCAG ATCCTGACCCGGCACTTCGCCCAGCAGCAGCCAATCACGGCCCGCTTCGGTCACCACATCCAGCACCGCC GCACACGGAACACCGGTGGTGGCCAGCCAGCTCAGACGCGCCGCTTCATCCTGCAGCTCGTTCAGCGCAC CGCTCAGATCGGTTTTCACAAACAGCACCGGACGACCCTGCGCGCT CAGACGAAACACCGCCGCATCAGA GCAGCCAATGGTCTGCTGCGCCCAATCATAGCCAAACAGACGTTCCACCCACGCTGCCGGGCTACCCGCA TGCAGGCCATCCTGTTCAATCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTC TCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCG AAAAGTGCCACCTAAATTGTAAGCGTTAATATTTTGTTAAAATTCGCGTTAAATTTTTGTTAAATCAGCT CATTTTTTAACCAATAGGCCGAAATCGGCAAAATCCCTTATAAATCAAAAGAATAGACCGAGATAGGGTT GAGTGGCCGCTACAGGGCGCTCCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGTTTCGGTGC GGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCC AGGGTTTTCCCAGTCACACGCGTAATACGACTCACTATAG Vector A555: GHsol-SGP-SGP-SGP-Gly-SGP-UL128-UL130-UL131 SGP-ATAGGCGGCGCATGAGAGAAGCCCAGACCAATTACCTACCCAAAATGGAGAAAGTTCACGTTGACATCGA GGAAGACAGCCCATTCCTCAGAGCTTTGCAGCGGAGCTTCCCGCAGTTTGAGGTAGAAGCCAAGCAGGTC ACTGATAATGACCATGCTAATGCCAGAGCGTTTTCGCATCTGGCTTCAAAACTGATCGAAACGGAGGTGG ACCCATCCGACACGATCCTTGACATTGGAAGTGCGCCCGCCCGCAGAATGTATTCTAAGCACAAGTATCA TTGTATCTGTCCGATGAGATGTGCGGAAGATCCGGACAGATTGTATAAGTATGCAACTAAGCTGAAGAAA AACTGTAAGGAAATAACTGATAAGGAATTGGACAAGAAAATGAAGGAGCTCGCCGCCGTCATGAGCGACC CTGACCTGGAAACTGAGACTATGTGCCTCCACGACGACGAGTCGTGTCGCTACGAAGGGCAAGTCGCTGT TTACCAGGATGTATACGCGGTTGACGGACCGACAAGTCTCTATCACCAAGCCAATAAGGGAGTTAGAGTC GCCTACTGGATAGGCTTTGACACCACCCCTTTTATGTTTAAGAACTTGGCTGGAGCATATCCATCATACT CTACCAACTGGGCCGACGAAACCGTGTTAACGGCTCGTAACATAGGCCTATGCAGCTCTGACGTTATGGA GCGGTCACGTAGAGGGATGTCCATTCTTAGAAAGAAGTATTTGAAACCATCCAACAATGTTCTATTCTCT GTTGGCTCGACCATCTACCACGAGAAGAGGGACTTACTGAGGAGCTGGCACCTGCCGTCTGTATTTCACT TACGTGGCAAGCAAAATTACACATGTCGGTGTGAGACTATAGTTAGTTGCGACGGGTACGTCGTTAAAAG AATAGCTATCAGTCCAGGCCTGTATGGGAA GCCTTCAGGCTATGCTGCTACGATGCACCGCGAGGGATTC TTGTGCTGCAAAGTGACAGACACATTGAACGGGGAGAGGGTCTCTTTTCCCGTGTGCACGTATGTGCCAG CTACATTGTGTGACCAAATGACTGGCATACTGGCAACAGATGTCAGTGCGGACGACGCGCAAAAACTGCT GGTTGGGCTCAACCAGCGTATAGTCGTCAACGGTCGCACCCAGAGAAACACCAATACCATGAAAAATTAC CTTTTGCCCGTAGTGGCCCAGGCATTTGCTAGGTGGGCAAAGGAATATAAGGAAGATCAAGAAGATGAAA GGCCACTAGGACTACGAGATAGACAGTTAGTCATGGGGTGTTGTTGGGCTTTTAGAAGGCACAAGATAAC ATCTATTTATAAGCGCCCGGATACCCAAACCATCATCAAAGTGAACAGCGATTTCCACTCATTCGTGCTG CCCAGGATAGGCAGTAACACATTGGAGATCGGGCTGAGAACAAGAATCAGGAAAATGTTAGAGGAGCACA AGGAGCCGTCACCTCTCATTACCGCCGAGGACGTACAAGAAGCTAAGTGCGCAGCCGATGAGGCTAAGGA GGTGCGTGAAGCCGAGGAGTTGCGCGCAGCTCTACCACCTTTGGCAGCTGATGTTGAGGAGCCCACTCTG GAAGCCGATGTAGACTTGATGTTACAAGAGGCTGGGGCCGGCTCAGTGGAGACACCTCGTGGCTTGATAA AGGTTACCAGCTACGATGGCGAGGACAAGATCGGCTCTTACGCTGTGCTTTCTCCGCAGGCTGTACTCAA GAGTGAAAAATTATCTTGCATCCACCCTCTCGCTGAACAAGTCATAGTGATAACACACTCTGGCCGAAAA GGGCGTTATGCCGTGGAACCATACCATGGTAAAGTAGTGGTGCCAGAGGGACATGCAATACCCGTCCAGG ACTTTCAAGCTCTGAGTGAAAGTGCCACCATTGTGT ACAACGAACGTGAGTTCGTAAACAGGTACCTGCA CCATATTGCCACACATGGAGGAGCGCTGAACACTGATGAAGAATATTACAAAACTGTCAAGCCCAGCGAG CACGACGGCGAATACCTGTACGACATCGACAGGAAACAGTGCGTCAAGAAAGAACTAGTCACTGGGCTAG GGCTCACAGGCGAGCTGGTGGATCCTCCCTTCCATGAATTCGCCTACGAGAGTCTGAGAACACGACCAGC CGCTCCTTACCAAGTACCAACCATAGGGGTGTATGGCGTGCCAGGATCAGGCAAGTCTGGCATCATTAAA AGCGCAGTCACCAAAAAAGATCTAGTGGTGAGCGCCAAGAAAGAAAACTGTGCAGAAATTATAAGGGACG TCAAGAAAATGAAAGGGCTGGACGTCAATGCCAGAACTGTGGACTCAGTGCTCTTGAATGGATGCAAACA CCCCGTAGAGACCCTGTATATTGACGAAGCTTTTGCTTGTCATGCAGGTACTCTCAGAGCGCTCATAGCC ATTATAAGACCTAAAAAGGCAGTGCTCTGCGGGGATCCCAAACAGTGCGGTTTTTTTAACATGATGTGCC TGAAAGTGCATTTTAACCACGAGATTTGCACACAAGTCTTCCACAAAAGCATCTCTCGCCGTTGCACTAA ATCTGTGACTTCGGTCGTCTCAACCTTGTTTTACGACAAAAAAATGAGAACGACGAATCCGAAAGAGACT AAGATTGTGATTGACACTACCGGCAGTACCAAACCTAAGCAGGACGATCTCATTCTCACTTGTTTCAGAG GGTGGGTGAAGCAGTTGCAAATAGATTACAAAGGCAACGAAATAATGACGGCAGCTGCCTCTCAAGGGCT GACCCGTAAAGGTGTGTATGCCGTTCGGTACAAGGTGAATGAAAATCCTCTGTACGCACCCACCTCAGAA CATGTGAACGTCCTACTGACCCGCACGGAGGACCGCATCGTG TGGAAAACACTAGCCGGCGACCCATGGA TAAAAACACTGACTGCCAAGTACCCTGGGAATTTCACTGCCACGATAGAGGAGTGGCAAGCAGAGCATGA TGCCATCATGAGGCACATCTTGGAGAGACCGGACCCTACCGACGTCTTCCAGAATAAGGCAAACGTGTGT TGGGCCAAGGCTTTAGTGCCGGTGCTGAAGACCGCTGGCATAGACATGACCACTGAACAATGGAACACTG TGGATTATTTTGAAACGGACAAAGCTCACTCAGCAGAGATAGTATTGAACCAACTATGCGTGAGGTTCTT TGGACTCGATCTGGACTCCGGTCTATTTTCTGCACCCACTGTTCCGTTATCCATTAGGAATAATCACTGG GATAACTCCCCGTCGCCTAACATGTACGGGCTGAATAAAGAAGTGGTCCGTCAGCTCTCTCGCAGGTACC CACAACTGCCTCGGGCAGTTGCCACTGGAAGAGTCTATGACATGAACACTGGTACACTGCGCAATTATGA TCCGCGCATAAACCTAGTACCTGTAAACAGAAGACTGCCTCATGCTTTAGTCCTCCACCATAATGAACAC CCACAGAGTGACTTTTCTTCATTCGTCAGCAAATTGAAGGGCAGAACTGTCCTGGTGGTCGGGGAAAAGT TGTCCGTCCCAGGCAAAATGGTTGACTGGTTGTCAGACCGGCCTGAGGCTACCTTCAGAGCTCGGCTGGA TTTAGGCATCCCAGGTGATGTGCCCAAATATGACATAATATTTGTTAATGTGAGGACCCCATATAAATAC CATCACTATCAGCAGTGTGAAGACCATGCCATTAAGCTTAGCATGTTGACCAAGAAAGCTTGTCTGCATC TGAATCCCGGCGGAACCTGTGTCAGCATAGGTTATGGTTACGCTGACAGGGCCAGCGAAAGCATCATTGG TGCTATAGCGCGGCAGTTCAAGTTTTCCCGGGTATGCAAACCGAAATC CTCACTTGAAGAGACGGAAGTT CTGTTTGTATTCATTGGGTACGATCGCAAGGCCCGTACGCACAATCCTTACAAGCTTTCATCAACCTTGA CCAACATTTATACAGGTTCCAGACTCCACGAAGCCGGATGTGCACCCTCATATCATGTGGTGCGAGGGGA TATTGCCACGGCCACCGAAGGAGTGATTATAAATGCTGCTAACAGCAAAGGACAACCTGGCGGAGGGGTG TGCGGAGCGCTGTATAAGAAATTCCCGGAAAGCTTCGATTTACAGCCGATCGAAGTAGGAAAAGCGCGAC TGGTCAAAGGTGCAGCTAAACATATCATTCATGCCGTAGGACCAAACTTCAACAAAGTTTCGGAGGTTGA AGGTGACAAACAGTTGGCAGAGGCTTATGAGTCCATCGCTAAGATTGTCAACGATAACAATTACAAGTCA GTAGCGATTCCACTGTTGTCCACCGGCATCTTTTCCGGGAACAAAGATCGACTAACCCAATCATTGAACC ATTTGCTGACAGCTTTAGACACCACTGATGCAGATGTAGCCATATACTGCAGGGACAAGAAATGGGAAAT GACTCTCAAGGAAGCAGTGGCTAGGAGAGAAGCAGTGGAGGAGATATGCATATCCGACGACTCTTCAGTG ACAGAACCTGATGCAGAGCTGGTGAGGGTGCATCCGAAGAGTTCTTTGGCTGGAAGGAAGGGCTACAGCA CAAGCGATGGCAAAACTTTCTCATATTTGGAAGGGACCAAGTTTCACCAGGCGGCCAAGGATATAGCAGA AATTAATGCCATGTGGCCCGTTGCAACGGAGGCCAATGAGCAGGTATGCATGTATATCCTCGGAGAAAGC ATGAGCAGTATTAGGTCGAAATGCCCCGTCGAAGAGTCGGAAGCCTCCACACCACCTAGCACGCTGCCTT GCTTGTGCATCCATGCCATGACTCCAGAAAGAGTACAGCGCCTAAAAGCCTCAC GTCCAGAACAAATTAC TGTGTGCTCATCCTTTCCATTGCCGAAGTATAGAATCACTGGTGTGCAGAAGATCCAATGCTCCCAGCCT ATATTGTTCTCACCGAAAGTGCCTGCGTATATTCATCCAAGGAAGTATCTCGTGGAAACACCACCGGTAG ACGAGACTCCGGAGCCATCGGCAGAGAACCAATCCACAGAGGGGACACCTGAACAACCACCACTTATAAC CGAGGATGAGACCAGGACTAGAACGCCTGAGCCGATCATCATCGAAGAGGAAGAAGAGGATAGCATAAGT TTGCTGTCAGATGGCCCGACCCACCAGGTGCTGCAAGTCGAGGCAGACATTCACGGGCCGCCCTCTGTAT CTAGCTCATCCTGGTCCATTCCTCATGCATCCGACTTTGATGTGGACAGTTTATCCATACTTGACACCCT GGAGGGAGCTAGCGTGACCAGCGGGGCAACGTCAGCCGAGACTAACTCTTACTTCGCAAAGAGTATGGAG TTTCTGGCGCGACCGGTGCCTGCGCCTCGAACAGTATTCAGGAACCCTCCACATCCCGCTCCGCGCACAA GAACACCGTCACTTGCACCCAGCAGGGCCTGCTCGAGAACCAGCCTAGTTTCCACCCCGCCAGGCGTGAA TAGGGTGATCACTAGAGAGGAGCTCGAGGCGCTTACCCCGTCACGCACTCCTAGCAGGTCGGTCTCGAGA ACCAGCCTGGTCTCCAACCCGCCAGGCGTAAATAGGGTGATTACAAGAGAGGAGTTTGAGGCGTTCGTAG CACAACAACAATGACGGTTTGATGCGGGTGCATACATCTTTTCCTCCGACACCGGTCAAGGGCATTTACA ACAAAAATCAGTAAGGCAAACGGTGCTATCCGAAGTGGTGTTGGAGAGGACCGAATTGGAGATTTCGTAT GCCCCGCGCCTCGACCAAGAAAAAGAAGAATTACTACGCAAGAAATTACAGTTAAATCCC ACACCTGCTA ACAGAAGCAGATACCAGTCCAGGAAGGTGGAGAACATGAAAGCCATAACAGCTAGACGTATTCTGCAAGG CCTAGGGCATTATTTGAAGGCAGAAGGAAAAGTGGAGTGCTACCGAACCCTGCATCCTGTTCCTTTGTAT TCATCTAGTGTGAACCGTGCCTTTTCAAGCCCCAAGGTCGCAGTGGAAGCCTGTAACGCCATGTTGAAAG AGAACTTTCCGACTGTGGCTTCTTACTGTATTATTCCAGAGTACGATGCCTATTTGGACATGGTTGACGG AGCTTCATGCTGCTTAGACACTGCCAGTTTTTGCCCTGCAAAGCTGCGCAGCTTTCCAAAGAAACACTCC TATTTGGAACCCACAATACGATCGGCAGTGCCTTCAGCGATCCAGAACACGCTCCAGAACGTCCTGGCAG CTGCCACAAAAAGAAATTGCAATGTCACGCAAATGAGAGAATTGCCCGTATTGGATTCGGCGGCCTTTAA TGTGGAATGCTTCAAGAAATATGCGTGTAATAATGAATATTGGGAAACGTTTAAAGAAAACCCCATCAGG CTTACTGAAGAAAACGTGGTAAATTACATTACCAAATTAAAAGGACCAAAAGCTGCTGCTCTTTTTGCGA AGACACATAATTTGAATATGTTGCAGGACATACCAATGGACAGGTTTGTAATGGACTTAAAGAGAGACGT GAAAGTGACTCCAGGAACAAAACATACTGAAGAACGGCCCAAGGTACAGGTGATCCAGGCTGCCGATCCG CTAGCAACAGCGTATCTGTGCGGAATCCACCGAGAGCTGGTTAGGAGATTAAATGCGGTCCTGCTTCCGA ACATTCATACACTGTTTGATATGTCGGCTGAAGACTTTGACGCTATTATAGCCGAGCACTTCCAGCCTGG GGATTGTGTTCTGGAAACTGACATCGCGTCGTTTGATAAAAGTGAGGACGACGCCATGGCTCTGAC CGCG TTAATGATTCTGGAAGACTTAGGTGTGGACGCAGAGCTGTTGACGCTGATTGAGGCGGCTTTCGGCGAAA TTTCATCAATACATTTGCCCACTAAAACTAAATTTAAATTCGGAGCCATGATGAAATCTGGAATGTTCCT CACACTGTTTGTGAACACAGTCATTAACATTGTAATCGCAAGCAGAGTGTTGAGAGAACGGCTAACCGGA TCACCATGTGCAGCATTCATTGGAGATGACAATATCGTGAAAGGAGTCAAATCGGACAAATTAATGGCAG ACAGGTGCGCCACCTGGTTGAATATGGAAGTCAAGATTATAGATGCTGTGGTGGGCGAGAAAGCGCCTTA TTTCTGTGGAGGGTTTATTTTGTGTGACTCCGTGACCGGCACAGCGTGCCGTGTGGCAGACCCCCTAAAA AGGCTGTTTAAGCTTGGCAAACCTCTGGCAGCAGACGATGAACATGATGATGACAGGAGAAGGGCATTGC ATGAAGAGTCAACACGCTGGAACCGAGTGGGTATTCTTTCAGAGCTGTGCAAGGCAGTAGAATCAAGGTA TGAAACCGTAGGAACTTCCATCATAGTTATGGCCATGACTACTCTAGCTAGCAGTGTTAAATCATTCAGC TACCTGAGAGGGGCCCCTATAACTCTCTACGGCTAACCTGAATGGACTACGACATAGTCTAGTCCGCCAA GATGAGGCCTGGCCTGCCCTCCTACCTGATCATCCTGGCCGTGTGCCTGTTCAGCCACCTGCTGTCCAGC AGATACGGCGCCGAGGCCGTGAGCGAGCCCCTGGACAAGGCTTTCCACCTGCTGCTGAACACCTACGGCA GACCCATCCGGTTTCTGCGGGAGAACACCACCCAGTGCACCTACAACAGCAGCCTGCGGAACAGCACCGT The CGTGAGAGAGAACGCCATCAGCTTCAACTTTTTCCAGAGCTACAACCAGTACTACGTGTTCCACATGCCC GATGCCTGTTTGCCGGCCCTCTGGCCGAGCAGTTCCTGAACCAGGTGGACCTGACCGAGACACTGGAAA GATACCAGCAGCGGCTGAATACCTACGCCCTGGTGTCCAAGGACCTGGCCAGCTACCGGTCCTTTAGCCA GCAGCTCAAGGCTCAGGATAGCCTCGGCGAGCAGCCTACCACCGTGCCCCCTCCCATCGACCTGAGCATC CCCCACGTGTGGATGCCTCCCCAGACCACCCCTCACGGCTGGACCGAGAGCCACACCACCTCCGGCCTGC ACAGACCCCACTTCAACCAGACCTGCATCCTGTTCGACGGCCACGACCTGCTGTTTAGCACCGTGACCCC CTGCCTGCACCAGGGCTTCTACCTGATCGACGAGCTGAGATACGTGAAGATCACCCTGACCGAGGATTTC TTCGTGGTCACCGTGTCCATCGACGACGACACCCCCATGCTGCTGATCTTCGGCCACCTGCCCAGAGTGC TGTTCAAGGCCCCCTACCAGCGGGACAACTTCATCCTGCGGCAGACCGAGAAGCACGAGCTGCTGGTGCT GGTCAAGAAGGACCAGCTGAACCGGCACTCCTACCTGAAGGACCCCGACTTCCTGGACGCCGCCCTGGAC TTCAACTACCTGGACCTGAGCGCCCTGCTGAGAAACAGCTTCCACAGATACGCCGTGGACGTGCTGAAGT CCGGACGGTGCCAGATGCTCGATCGGCGGACCGTGGAGATGGCCTTCGCCTATGCCCTCGCCCTGTTCGC CGCTGCCAGACAGGAAGAGGCTGGCGCCCAGGTGTCAGTGCCCAGAGCCCTGGATAGACAGGCCGCCCTG CTGCAGATCCAGGAATTCATGATCACCTGCCTGAGCCAGACCCCCCCTAGAACCACCCTGCTGCTGTACC CCACAGCCGTGGATCTGGCCAAGAGGGCCCTGTGGACCCCCAACCAGATCACCGACATCACAAGCCTCGT GCGGCTC GTGTACATCCTGAGCAAGCAGAACCAGCAGCACCTGATCCCCCAGTGGGCCCTGAGACAGATC GCCGACTTCGCCCTGAAGCTGCACAAGACCCATCTGGCCAGCTTTCTGAGCGCCTTCGCCAGGCAGGAAC TGTACCTGATGGGCAGCCTGGTCCACAGCATGCTGGTGCATACCACCGAGCGGCGGGAGATCTTCATCGT GGAGACAGGCCTGTGTAGCCTGGCCGAGCTGTCCCACTTTACCCAGCTGCTGGCCCACCCTCACCACGAG TACCTGAGCGACCTGTACACCCCCTGCAGCAGCAGCGGCAGACGGGACCACAGCCTGGAACGGCTGACCA GACTGTTCCCCGATGCCACCGTGCCTGCTACAGTGCCTGCCGCCCTGTCCATCCTGTCCACCATGCAGCC CAGCACCCTGGAAACCTTCCCCGACCTGTTCTGCCTGCCCCTGGGCGAGAGCTTTAGCGCCCTGACCGTG TCCGAGCACGTGTCCTACATCGTGACCAATCAGTACCTGATCAAGGGCATCAGCTACCCCGTGTCCACCA CAGTCGTGGGCCAGAGCCTGATCATCACCCAGACCGACAGCCAGACCAAGTGCGAGCTGACCCGGAACAT GCACACCACACACAGCATCACCGTGGCCCTGAACATCAGCCTGGAAAACTGCGCTTTCTGTCAGTCTGCC CTGCTGGAATACGACGATACCCAGGGCGTGATCAACATCATGTACATGCACGACAGCGACGACGTGCTGT TCGCCCTGGACCCCTACAACGAGGTGGTGGTGTCCAGCCCCCGGACCCACTACCTGATGCTGCTGAAGAA CGGCACCGTGCTGGAAGTGACCGACGTGGTGGTGGACGCCACCGACTGATAATCTAGAGGCCCCTATAAC TCTCTACGGCTAACCTGAATGGACTACGACATAGTCTAGTCCGCCAAGATGTGCAGAAGGCCCGACTGCG GCTTCAGCTTCAG CCCTGGACCCGTGATCCTGCTGTGGTGCTGCCTGCTGCTGCCTATCGTGTCCTCTGC CGCCGTGTCTGTGGCCCCTACAGCCGCCGAGAAGGTGCCAGCCGAGTGCCCCGAGCTGACCAGAAGATGC CTGCTGGGCGAGGTGTTCGAGGGCGACAAGTACGAGAGCTGGCTGCGGCCCCTGGTCAACGTGACCGGCA GAGATGGCCCCCTGAGCCAGCTGATCCGGTACAGACCCGTGACCCCCGAGGCCGCCAATAGCGTGCTGCT GGACGAGGCCTTCCTGGATACCCTGGCCCTGCTGTACAACAACCCCGACCAGCTGAGAGCCCTGCTGACC CTGCTGTCCAGCGACACCGCCCCCAGATGGATGACCGTGATGCGGGGCTACAGCGAGTGTGGAGATGGCA GCCCTGCCGTGTACACCTGCGTGGACGACCTGTGCAGAGGCTACGACCTGACCAGACTGAGCTACGGCCG GTCCATCTTCACAGAGCACGTGCTGGGCTTCGAGCTGGTGCCCCCCAGCCTGTTCAACGTGGTGGTGGCC ATCCGGAACGAGGCCACCAGAACCAACAGAGCCGTGCGGCTGCCTGTGTCTACAGCCGCTGCACCTGAGG GCATCACACTGTTCTACGGCCTGTACAACGCCGTGAAAGAGTTCTGCCTCCGGCACCAGCTGGATCCCCC CCTGCTGAGACACCTGGACAAGTACTACGCCGGCCTGCCCCCAGAGCTGAAGCAGACCAGAGTGAACCTG CCCGCCCACAGCAGATATGGCCCTCAGGCCGTGGACGCCAGATGATAACGCCGGCGGCCCCTATAACTCT CTACGGCTAACCTGAATGGACTACGACATAGTCTAGTCCGCCAAGATGAGCCCCAAGGACCTGACCCCCT TCCTGACAACCCTGTGGCTGCTCCTGGGCCATAGCAGAGTGCCTAGAGTGCGGGCCGAGGAATGCTGCGA GTTCATCAACGTGAACCAC CCCCCCGAGCGGTGCTACGACTTCAAGATGTGCAACCGGTTCACCGTGGCC CTGAGATGCCCCGACGGCGAAGTGTGCTACAGCCCCGAGAAAACCGCCGAGATCCGGGGCATCGTGACCA CCATGACCCACAGCCTGACCCGGCAGGTGGTGCACAACAAGCTGACCAGCTGCAACTACAACCCCCTGTA CCTGGAAGCCGACGGCCGGATCAGATGCGGCAAAGTGAACGACAAGGCCCAGTACCTGCTGGGAGCCGCC GGAAGCGTGCCCTACCGGTGGATCAACCTGGAATACGACAAGATCACCCGGATCGTGGGCCTGGACCAGT ACCTGGAAAGCGTGAAGAAGCACAAGCGGCTGGACGTGTGCAGAGCCAAGATGGGCTACATGCTGCAGTG ATAAGGCGCGCCAACGTTACTGGCCGAAGCCGCTTGGAATAAGGCCGGTGTGCGTTTGTCTATATGTTAT TTTCCACCATATTGCCGTCTTTTGGCAATGTGAGGGCCCGGAAACCTGGCCCTGTCTTCTTGACGAGCAT TCCTAGGGGTCTTTCCCCTCTCGCCAAAGGAATGCAAGGTCTGTTGAATGTCGTGAAGGAAGCAGTTCCT CTGGAAGCTTCTTGAAGACAAACAACGTCTGTAGCGACCCTTTGCAGGCAGCGGAACCCCCCACCTGGCG ACAGGTGCCTCTGCGGCCAAAAGCCACGTGTATAAGATACACCTGCAAAGGCGGCACAACCCCAGTGCCA CGTTGTGAGTTGGATAGTTGTGGAAAGAGTCAAATGGCTCTCCTCAAGCGTATTCAACAAGGGGCTGAAG GATGCCCAGAAGGTACCCCATTGTATGGGATCTGATCTGGGGCCTCGGTGCACATGCTTTACATGTGTTT AGTCGAGGTTAAAAAAACGTCTAGGCCCCCCGAACCACGGGGACGTGGTTTTCCTTTGAAAAACACGATA ATATGCTGCGGCTGCTGCTGAGACA CCACTTCCACTGCCTGCTGCTGTGTGCCGTGTGGGCCACCCCTTG TCTGGCCAGCCCTTGGAGCACCCTGACCGCCAACCAGAACCCTAGCCCCCCTTGGTCCAAGCTGACCTAC AGCAAGCCCCACGACGCCGCCACCTTCTACTGCCCCTTTCTGTACCCCAGCCCTCCCAGAAGCCCCCTGC AGTTCAGCGGCTTCCAGAGAGTGTCCACCGGCCCTGAGTGCCGGAACGAGACACTGTACCTGCTGTACAA CCGGGAGGGCCAGACACTGGTGGAGCGGAGCAGCACCTGGGTGAAAAAAGTGATCTGGTATCTGAGCGGC CGGAACCAGACCATCCTGCAGCGGATGCCCAGAACCGCCAGCAAGCCCAGCGACGGCAACGTGCAGATCA GCGTGGAGGACGCCAAAATCTTCGGAGCCCACATGGTGCCCAAGCAGACCAAGCTGCTGAGATTCGTGGT CAACGACGGCACCAGATATCAGATGTGCGTGATGAAGCTGGAAAGCTGGGCCCACGTGTTCCGGGACTAC TCCGTGAGCTTCCAGGTCCGGCTGACCTTCACCGAGGCCAACAACCAGACCTACACCTTCTGCACCCACC CCAACCTGATCGTGTGATAAGTACCTTTGTACGCCTGTTTTATACCCCCTCCCTGATTTGCAACTTAGAA GCAACGCAAACCAGATCAATAGTAGGTGTGACATACCAGTCGCATCTTGATCAAGCACTTCTGTATCCCC GGACCGAGTATCAATAGACTGTGCACACGGTTGAAGGAGAAAACGTCCGTTACCCGGCTAACTACTTCGA GAAGCCTAGTAACGCCATTGAAGTTGCAGAGTGTTTCGCTCAGCACTCCCCCCGTGTAGATCAGGTCGAT GAGTCACCGCATTCCCCACGGGCGACCGTGGCGGTGGCTGCGTTGGCGGCCTGCCTATGGGGTAACCCAT AGGACGCTCTAATACGGACATGGCGTGAAGA GTCTATTGAGCTAGTTAGTAGTCCTCCGGCCCCTGAATG CGGCTAATCCTAACTGCGGAGCACATACCCTTAATCCAAAGGGCAGTGTGTCGTAACGGGCAACTCTGCA GCGGAACCGACTACTTTGGGTGTCCGTGTTTCTTTTTATTCTTGTATTGGCTGCTTATGGTGACAATTAA AGAATTGTTACCATATAGCTATTGGATTGGCCATCCAGTGTCAAACAGAGCTATTGTATATCTCTTTGTT GGATTCACACCTCTCACTCTTGAAACGTTACACACCCTCAATTACATTATACTGCTGAACACGAAGCGCA TATGCGGCTGTGCAGAGTGTGGCTGTCCGTGTGCCTGTGTGCCGTGGTGCTGGGCCAGTGCCAGAGAGAG ACAGCCGAGAAGAACGACTACTACCGGGTGCCCCACTACTGGGATGCCTGCAGCAGAGCCCTGCCCGACC AGACCCGGTACAAATACGTGGAGCAGCTCGTGGACCTGACCCTGAACTACCACTACGACGCCAGCCACGG CCTGGACAACTTCGACGTGCTGAAGCGGATCAACGTGACCGAGGTGTCCCTGCTGATCAGCGACTTCCGG CGGCAGAACAGAAGAGGCGGCACCAACAAGCGGACCACCTTCAACGCCGCTGGCTCTCTGGCCCCTCACG CCAGATCCCTGGAATTCAGCGTGCGGCTGTTCGCCAACTGATAACGTTGCATCCTGCAGGATACAGCAGC AATTGGCAAGCTGCTTACATAGAACTCGCGGCGATTGGCATGCCGCCTTAAAATTTTTATTTTATTTTTC TTTTCTTTTCCGAATCGGATTTTGTTTTTAATATTTCAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAGGGTCGGCATGGCATCTCCACCTCCTCGCGGTCCGACCTGGGCATCCGAAGGAGGACGCACGTCCACT CGGATGGCTAAGGGAGAGCCACGTTTAAACGCTAGAG CAAGACGTTTCCCGTTGAATATGGCTCATAACA CCCCTTGTATTACTGTTTATGTAAGCAGACAGTTTTATTGTTCATGATGATATATTTTTATCTTGTGCAA TGTAACATCAGAGATTTTGAGACACAACGTGGCTTTGTTGAATAAATCGAACTTTTGCTGAGTTGAAGGA TCAGATCACGCATCTTCCCGACAACGCAGACCGTTCCGTGGCAAAGCAAAAGTTCAAAATCACCAACTGG TCCACCTACAACAAAGCTCTCATCAACCGTGGCTCCCTCACTTTCTGGCTGGATGATGGGGCGATTCAGG CCTGGTATGAGTCAGCAACACCTTCTTCACGAGGCAGACCTCAGCGCTAGCGGAGTGTATACTGGCTTAC TATGTTGGCACTGATGAGGGTGTCAGTGAAGTGCTTCATGTGGCAGGAGAAAAAAGGCTGCACCGGTGCG TCAGCAGAATATGTGATACAGGATATATTCCGCTTCCTCGCTCACTGACTCGCTACGCTCGGTCGTTCGA CTGCGGCGAGCGGAAATGGCTTACGAACGGGGCGGAGATTTCCTGGAAGATGCCAGGAAGATACTTAACA GGGAAGTGAGAGGGCCGCGGCAAAGCCGTTTTTCCATAGGCTCCGCCCCCCTGACAAGCATCACGAAATC TGACGCTCAAATCAGTGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCTGGCGGCTC CCTCGTGCGCTCTCCTGTTCCTGCCTTTCGGTTTACCGGTGTCATTCCGCTGTTATGGCCGCGTTTGTCT CATTCCACGCCTGACACTCAGTTCCGGGTAGGCAGTTCGCTCCAAGCTGGACTGTATGCACGAACCCCCC GTTCAGTCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGAAAGACATGCAAAAG CACCACTGGCAGCAGCCACTGGTAATTGATTTAGAGGAGTTAG TCTTGAAGTCATGCGCCGGTTAAGGCT AAACTGAAAGGACAAGTTTTGGTGACTGCGCTCCTCCAAGCCAGTTACCTCGGTTCAAAGAGTTGGTAGC TCAGAGAACCTTCGAAAAACCGCCCTGCAAGGCGGTTTTTTCGTTTTCAGAGCAAGAGATTACGCGCAGA CCAAAACGATCTCAAGAAGATCATCTTATTAAGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAG GGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAA ATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTATTAGAAAAATTCATCCAGCAGACGATAA AACGCAATACGCTGGCTATCCGGTGCCGCAATGCCATACAGCACCAGAAAACGATCCGCCCATTCGCCGC CCAGTTCTTCCGCAATATCACGGGTGGCCAGCGCAATATCCTGATAACGATCCGCCACGCCCAGACGGCC GCAATCAATAAAGCCGCTAAAACGGCCATTTTCCACCATAATGTTCGGCAGGCACGCATCACCATGGGTC ACCACCAGATCTTCGCCATCCGGCATGCTCGCTTTCAGACGCGCAAACAGCTCTGCCGGTGCCAGGCCCT GATGTTCTTCATCCAGATCATCCTGATCCACCAGGCCCGCTTCCATACGGGTACGCGCACGTTCAATACG ATGTTTCGCCTGATGATCAAACGGACAGGTCGCCGGGTCCAGGGTATGCAGACGACGCATGGCATCCGCC ATAATGCTCACTTTTTCTGCCGGCGCCAGATGGCTAGACAGCAGATCCTGACCCGGCACTTCGCCCAGCA GCAGCCAATCACGGCCCGCTTCGGTCACCACATCCAGCACCGCCGCACACGGAACACCGGTGGTGGCCAG CCAGCTCAGACGCGCCGCTTCATCCTGCAGCTCGTTCAGCGCACCGCTC AGATCGGTTTTCACAAACAGC ACCGGACGACCCTGCGCGCTCAGACGAAACACCGCCGCATCAGAGCAGCCAATGGTCTGCTGCGCCCAAT CATAGCCAAACAGACGTTCCACCCACGCTGCCGGGCTACCCGCATGCAGGCCATCCTGTTCAATCATACT CTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGT ATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTAAATTGTAAGCGT TAATATTTTGTTAAAATTCGCGTTAAATTTTTGTTAAATCAGCTCATTTTTTAACCAATAGGCCGAAATC GGCAAAATCCCTTATAAATCAAAAGAATAGACCGAGATAGGGTTGAGTGGCCGCTACAGGGCGCTCCCAT TCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGTTTCGGTGCGGGCCTCTTCGCTATTACGCCAGCTG GCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACACGCGTAAT ACGACTCACTATAG Vector A556: GHsol6His-SGP-SGP-SGP-Gly-SGP-UL128-UL130-UL131 SGP-ATAGGCGGCGCATGAGAGAAGCCCAGACCAATTACCTACCCAAAATGGAGAAAGTTCACGTTGACATCGA GGAAGACAGCCCATTCCTCAGAGCTTTGCAGCGGAGCTTCCCGCAGTTTGAGGTAGAAGCCAAGCAGGTC ACTGATAATGACCATGCTAATGCCAGAGCGTTTTCGCATCTGGCTTCAAAACTGATCGAAACGGAGGTGG ACCCATCCGACACGATCCTTGACATTGGAAGTGCGCCCGCCCGCAGAATGTATTCTAAGCACAAGTATCA TTGTATCTGTCCGATGAGATGTGCGGAAGATCCGGACAGATTGTATAAGTATGCAACTAAGCTGAAGAAA AACTGTAAGGAAATAACTGATAAGGAATTGGACAAGAAAATGAAGGAGCTCGCCGCCGTCATGAGCGACC CTGACCTGGAAACTGAGACTATGTGCCTCCACGACGACGAGTCGTGTCGCTACGAAGGGCAAGTCGCTGT TTACCAGGATGTATACGCGGTTGACGGACCGACAAGTCTCTATCACCAAGCCAATAAGGGAGTTAGAGTC GCCTACTGGATAGGCTTTGACACCACCCCTTTTATGTTTAAGAACTTGGCTGGAGCATATCCATCATACT CTACCAACTGGGCCGACGAAACCGTGTTAACGGCTCGTAACATAGGCCTATGCAGCTCTGACGTTATGGA GCGGTCACGTAGAGGGATGTCCATTCTTAGAAAGAAGTATTTGAAACCATCCAACAATGTTCTATTCTCT GTTGGCTCGACCATCTACCACGAGAAGAGGGACTTACTGAGGAGCTGGCACCTGCCGTCTGTATTTCACT TACGTGGCAAGCAAAATTACACATGTCGGTGTGAGACTATAGTTAGTTGCGACGGGTACGTCGTTAAAAG AATAGCTATCAGTCCAGGCCTGTATG GGAAGCCTTCAGGCTATGCTGCTACGATGCACCGCGAGGGATTC TTGTGCTGCAAAGTGACAGACACATTGAACGGGGAGAGGGTCTCTTTTCCCGTGTGCACGTATGTGCCAG CTACATTGTGTGACCAAATGACTGGCATACTGGCAACAGATGTCAGTGCGGACGACGCGCAAAAACTGCT GGTTGGGCTCAACCAGCGTATAGTCGTCAACGGTCGCACCCAGAGAAACACCAATACCATGAAAAATTAC CTTTTGCCCGTAGTGGCCCAGGCATTTGCTAGGTGGGCAAAGGAATATAAGGAAGATCAAGAAGATGAAA GGCCACTAGGACTACGAGATAGACAGTTAGTCATGGGGTGTTGTTGGGCTTTTAGAAGGCACAAGATAAC ATCTATTTATAAGCGCCCGGATACCCAAACCATCATCAAAGTGAACAGCGATTTCCACTCATTCGTGCTG CCCAGGATAGGCAGTAACACATTGGAGATCGGGCTGAGAACAAGAATCAGGAAAATGTTAGAGGAGCACA AGGAGCCGTCACCTCTCATTACCGCCGAGGACGTACAAGAAGCTAAGTGCGCAGCCGATGAGGCTAAGGA GGTGCGTGAAGCCGAGGAGTTGCGCGCAGCTCTACCACCTTTGGCAGCTGATGTTGAGGAGCCCACTCTG GAAGCCGATGTAGACTTGATGTTACAAGAGGCTGGGGCCGGCTCAGTGGAGACACCTCGTGGCTTGATAA AGGTTACCAGCTACGATGGCGAGGACAAGATCGGCTCTTACGCTGTGCTTTCTCCGCAGGCTGTACTCAA GAGTGAAAAATTATCTTGCATCCACCCTCTCGCTGAACAAGTCATAGTGATAACACACTCTGGCCGAAAA GGGCGTTATGCCGTGGAACCATACCATGGTAAAGTAGTGGTGCCAGAGGGACATGCAATACCCGTCCAGG ACTTTCAAGCTCTGAGTGAAAGTGCCACCATT GTGTACAACGAACGTGAGTTCGTAAACAGGTACCTGCA CCATATTGCCACACATGGAGGAGCGCTGAACACTGATGAAGAATATTACAAAACTGTCAAGCCCAGCGAG CACGACGGCGAATACCTGTACGACATCGACAGGAAACAGTGCGTCAAGAAAGAACTAGTCACTGGGCTAG GGCTCACAGGCGAGCTGGTGGATCCTCCCTTCCATGAATTCGCCTACGAGAGTCTGAGAACACGACCAGC CGCTCCTTACCAAGTACCAACCATAGGGGTGTATGGCGTGCCAGGATCAGGCAAGTCTGGCATCATTAAA AGCGCAGTCACCAAAAAAGATCTAGTGGTGAGCGCCAAGAAAGAAAACTGTGCAGAAATTATAAGGGACG TCAAGAAAATGAAAGGGCTGGACGTCAATGCCAGAACTGTGGACTCAGTGCTCTTGAATGGATGCAAACA CCCCGTAGAGACCCTGTATATTGACGAAGCTTTTGCTTGTCATGCAGGTACTCTCAGAGCGCTCATAGCC ATTATAAGACCTAAAAAGGCAGTGCTCTGCGGGGATCCCAAACAGTGCGGTTTTTTTAACATGATGTGCC TGAAAGTGCATTTTAACCACGAGATTTGCACACAAGTCTTCCACAAAAGCATCTCTCGCCGTTGCACTAA ATCTGTGACTTCGGTCGTCTCAACCTTGTTTTACGACAAAAAAATGAGAACGACGAATCCGAAAGAGACT AAGATTGTGATTGACACTACCGGCAGTACCAAACCTAAGCAGGACGATCTCATTCTCACTTGTTTCAGAG GGTGGGTGAAGCAGTTGCAAATAGATTACAAAGGCAACGAAATAATGACGGCAGCTGCCTCTCAAGGGCT GACCCGTAAAGGTGTGTATGCCGTTCGGTACAAGGTGAATGAAAATCCTCTGTACGCACCCACCTCAGAA CATGTGAACGTCCTACTGACCCGCACGGAGGACCGCAT CGTGTGGAAAACACTAGCCGGCGACCCATGGA TAAAAACACTGACTGCCAAGTACCCTGGGAATTTCACTGCCACGATAGAGGAGTGGCAAGCAGAGCATGA TGCCATCATGAGGCACATCTTGGAGAGACCGGACCCTACCGACGTCTTCCAGAATAAGGCAAACGTGTGT TGGGCCAAGGCTTTAGTGCCGGTGCTGAAGACCGCTGGCATAGACATGACCACTGAACAATGGAACACTG TGGATTATTTTGAAACGGACAAAGCTCACTCAGCAGAGATAGTATTGAACCAACTATGCGTGAGGTTCTT TGGACTCGATCTGGACTCCGGTCTATTTTCTGCACCCACTGTTCCGTTATCCATTAGGAATAATCACTGG GATAACTCCCCGTCGCCTAACATGTACGGGCTGAATAAAGAAGTGGTCCGTCAGCTCTCTCGCAGGTACC CACAACTGCCTCGGGCAGTTGCCACTGGAAGAGTCTATGACATGAACACTGGTACACTGCGCAATTATGA TCCGCGCATAAACCTAGTACCTGTAAACAGAAGACTGCCTCATGCTTTAGTCCTCCACCATAATGAACAC CCACAGAGTGACTTTTCTTCATTCGTCAGCAAATTGAAGGGCAGAACTGTCCTGGTGGTCGGGGAAAAGT TGTCCGTCCCAGGCAAAATGGTTGACTGGTTGTCAGACCGGCCTGAGGCTACCTTCAGAGCTCGGCTGGA TTTAGGCATCCCAGGTGATGTGCCCAAATATGACATAATATTTGTTAATGTGAGGACCCCATATAAATAC CATCACTATCAGCAGTGTGAAGACCATGCCATTAAGCTTAGCATGTTGACCAAGAAAGCTTGTCTGCATC TGAATCCCGGCGGAACCTGTGTCAGCATAGGTTATGGTTACGCTGACAGGGCCAGCGAAAGCATCATTGG TGCTATAGCGCGGCAGTTCAAGTTTTCCCGGGTATGCAAACCGA AATCCTCACTTGAAGAGACGGAAGTT CTGTTTGTATTCATTGGGTACGATCGCAAGGCCCGTACGCACAATCCTTACAAGCTTTCATCAACCTTGA CCAACATTTATACAGGTTCCAGACTCCACGAAGCCGGATGTGCACCCTCATATCATGTGGTGCGAGGGGA TATTGCCACGGCCACCGAAGGAGTGATTATAAATGCTGCTAACAGCAAAGGACAACCTGGCGGAGGGGTG TGCGGAGCGCTGTATAAGAAATTCCCGGAAAGCTTCGATTTACAGCCGATCGAAGTAGGAAAAGCGCGAC TGGTCAAAGGTGCAGCTAAACATATCATTCATGCCGTAGGACCAAACTTCAACAAAGTTTCGGAGGTTGA AGGTGACAAACAGTTGGCAGAGGCTTATGAGTCCATCGCTAAGATTGTCAACGATAACAATTACAAGTCA GTAGCGATTCCACTGTTGTCCACCGGCATCTTTTCCGGGAACAAAGATCGACTAACCCAATCATTGAACC ATTTGCTGACAGCTTTAGACACCACTGATGCAGATGTAGCCATATACTGCAGGGACAAGAAATGGGAAAT GACTCTCAAGGAAGCAGTGGCTAGGAGAGAAGCAGTGGAGGAGATATGCATATCCGACGACTCTTCAGTG ACAGAACCTGATGCAGAGCTGGTGAGGGTGCATCCGAAGAGTTCTTTGGCTGGAAGGAAGGGCTACAGCA CAAGCGATGGCAAAACTTTCTCATATTTGGAAGGGACCAAGTTTCACCAGGCGGCCAAGGATATAGCAGA AATTAATGCCATGTGGCCCGTTGCAACGGAGGCCAATGAGCAGGTATGCATGTATATCCTCGGAGAAAGC ATGAGCAGTATTAGGTCGAAATGCCCCGTCGAAGAGTCGGAAGCCTCCACACCACCTAGCACGCTGCCTT GCTTGTGCATCCATGCCATGACTCCAGAAAGAGTACAGCGCCTAAAAGCC TCACGTCCAGAACAAATTAC TGTGTGCTCATCCTTTCCATTGCCGAAGTATAGAATCACTGGTGTGCAGAAGATCCAATGCTCCCAGCCT ATATTGTTCTCACCGAAAGTGCCTGCGTATATTCATCCAAGGAAGTATCTCGTGGAAACACCACCGGTAG ACGAGACTCCGGAGCCATCGGCAGAGAACCAATCCACAGAGGGGACACCTGAACAACCACCACTTATAAC CGAGGATGAGACCAGGACTAGAACGCCTGAGCCGATCATCATCGAAGAGGAAGAAGAGGATAGCATAAGT TTGCTGTCAGATGGCCCGACCCACCAGGTGCTGCAAGTCGAGGCAGACATTCACGGGCCGCCCTCTGTAT CTAGCTCATCCTGGTCCATTCCTCATGCATCCGACTTTGATGTGGACAGTTTATCCATACTTGACACCCT GGAGGGAGCTAGCGTGACCAGCGGGGCAACGTCAGCCGAGACTAACTCTTACTTCGCAAAGAGTATGGAG TTTCTGGCGCGACCGGTGCCTGCGCCTCGAACAGTATTCAGGAACCCTCCACATCCCGCTCCGCGCACAA GAACACCGTCACTTGCACCCAGCAGGGCCTGCTCGAGAACCAGCCTAGTTTCCACCCCGCCAGGCGTGAA TAGGGTGATCACTAGAGAGGAGCTCGAGGCGCTTACCCCGTCACGCACTCCTAGCAGGTCGGTCTCGAGA ACCAGCCTGGTCTCCAACCCGCCAGGCGTAAATAGGGTGATTACAAGAGAGGAGTTTGAGGCGTTCGTAG CACAACAACAATGACGGTTTGATGCGGGTGCATACATCTTTTCCTCCGACACCGGTCAAGGGCATTTACA ACAAAAATCAGTAAGGCAAACGGTGCTATCCGAAGTGGTGTTGGAGAGGACCGAATTGGAGATTTCGTAT GCCCCGCGCCTCGACCAAGAAAAAGAAGAATTACTACGCAAGAAATTACAGTTAAA TCCCACACCTGCTA ACAGAAGCAGATACCAGTCCAGGAAGGTGGAGAACATGAAAGCCATAACAGCTAGACGTATTCTGCAAGG CCTAGGGCATTATTTGAAGGCAGAAGGAAAAGTGGAGTGCTACCGAACCCTGCATCCTGTTCCTTTGTAT TCATCTAGTGTGAACCGTGCCTTTTCAAGCCCCAAGGTCGCAGTGGAAGCCTGTAACGCCATGTTGAAAG AGAACTTTCCGACTGTGGCTTCTTACTGTATTATTCCAGAGTACGATGCCTATTTGGACATGGTTGACGG AGCTTCATGCTGCTTAGACACTGCCAGTTTTTGCCCTGCAAAGCTGCGCAGCTTTCCAAAGAAACACTCC TATTTGGAACCCACAATACGATCGGCAGTGCCTTCAGCGATCCAGAACACGCTCCAGAACGTCCTGGCAG CTGCCACAAAAAGAAATTGCAATGTCACGCAAATGAGAGAATTGCCCGTATTGGATTCGGCGGCCTTTAA TGTGGAATGCTTCAAGAAATATGCGTGTAATAATGAATATTGGGAAACGTTTAAAGAAAACCCCATCAGG CTTACTGAAGAAAACGTGGTAAATTACATTACCAAATTAAAAGGACCAAAAGCTGCTGCTCTTTTTGCGA AGACACATAATTTGAATATGTTGCAGGACATACCAATGGACAGGTTTGTAATGGACTTAAAGAGAGACGT GAAAGTGACTCCAGGAACAAAACATACTGAAGAACGGCCCAAGGTACAGGTGATCCAGGCTGCCGATCCG CTAGCAACAGCGTATCTGTGCGGAATCCACCGAGAGCTGGTTAGGAGATTAAATGCGGTCCTGCTTCCGA ACATTCATACACTGTTTGATATGTCGGCTGAAGACTTTGACGCTATTATAGCCGAGCACTTCCAGCCTGG GGATTGTGTTCTGGAAACTGACATCGCGTCGTTTGATAAAAGTGAGGACGACGCCATGGCTC TGACCGCG TTAATGATTCTGGAAGACTTAGGTGTGGACGCAGAGCTGTTGACGCTGATTGAGGCGGCTTTCGGCGAAA TTTCATCAATACATTTGCCCACTAAAACTAAATTTAAATTCGGAGCCATGATGAAATCTGGAATGTTCCT CACACTGTTTGTGAACACAGTCATTAACATTGTAATCGCAAGCAGAGTGTTGAGAGAACGGCTAACCGGA TCACCATGTGCAGCATTCATTGGAGATGACAATATCGTGAAAGGAGTCAAATCGGACAAATTAATGGCAG ACAGGTGCGCCACCTGGTTGAATATGGAAGTCAAGATTATAGATGCTGTGGTGGGCGAGAAAGCGCCTTA TTTCTGTGGAGGGTTTATTTTGTGTGACTCCGTGACCGGCACAGCGTGCCGTGTGGCAGACCCCCTAAAA AGGCTGTTTAAGCTTGGCAAACCTCTGGCAGCAGACGATGAACATGATGATGACAGGAGAAGGGCATTGC ATGAAGAGTCAACACGCTGGAACCGAGTGGGTATTCTTTCAGAGCTGTGCAAGGCAGTAGAATCAAGGTA TGAAACCGTAGGAACTTCCATCATAGTTATGGCCATGACTACTCTAGCTAGCAGTGTTAAATCATTCAGC TACCTGAGAGGGGCCCCTATAACTCTCTACGGCTAACCTGAATGGACTACGACATAGTCTAGTCCGCCAA GATGAGGCCTGGCCTGCCCTCCTACCTGATCATCCTGGCCGTGTGCCTGTTCAGCCACCTGCTGTCCAGC AGATACGGCGCCGAGGCCGTGAGCGAGCCCCTGGACAAGGCTTTCCACCTGCTGCTGAACACCTACGGCA GACCCATCCGGTTTCTGCGGGAGAACACCACCCAGTGCACCTACAACAGCAGCCTGCGGAACAGCACCGT CGTGAGAGAGAACGCCATCAGCTTCAACTTTTTCCAGAGCTACAACCAGTACTACGTGTTCCACATGC CC AGATGCCTGTTTGCCGGCCCTCTGGCCGAGCAGTTCCTGAACCAGGTGGACCTGACCGAGACACTGGAAA GATACCAGCAGCGGCTGAATACCTACGCCCTGGTGTCCAAGGACCTGGCCAGCTACCGGTCCTTTAGCCA GCAGCTCAAGGCTCAGGATAGCCTCGGCGAGCAGCCTACCACCGTGCCCCCTCCCATCGACCTGAGCATC CCCCACGTGTGGATGCCTCCCCAGACCACCCCTCACGGCTGGACCGAGAGCCACACCACCTCCGGCCTGC ACAGACCCCACTTCAACCAGACCTGCATCCTGTTCGACGGCCACGACCTGCTGTTTAGCACCGTGACCCC CTGCCTGCACCAGGGCTTCTACCTGATCGACGAGCTGAGATACGTGAAGATCACCCTGACCGAGGATTTC TTCGTGGTCACCGTGTCCATCGACGACGACACCCCCATGCTGCTGATCTTCGGCCACCTGCCCAGAGTGC TGTTCAAGGCCCCCTACCAGCGGGACAACTTCATCCTGCGGCAGACCGAGAAGCACGAGCTGCTGGTGCT GGTCAAGAAGGACCAGCTGAACCGGCACTCCTACCTGAAGGACCCCGACTTCCTGGACGCCGCCCTGGAC TTCAACTACCTGGACCTGAGCGCCCTGCTGAGAAACAGCTTCCACAGATACGCCGTGGACGTGCTGAAGT CCGGACGGTGCCAGATGCTCGATCGGCGGACCGTGGAGATGGCCTTCGCCTATGCCCTCGCCCTGTTCGC CGCTGCCAGACAGGAAGAGGCTGGCGCCCAGGTGTCAGTGCCCAGAGCCCTGGATAGACAGGCCGCCCTG CTGCAGATCCAGGAATTCATGATCACCTGCCTGAGCCAGACCCCCCCTAGAACCACCCTGCTGCTGTACC CCACAGCCGTGGATCTGGCCAAGAGGGCCCTGTGGACCCCCAACCAGATCACCGACATCACAAGCCTCGT GCG GCTCGTGTACATCCTGAGCAAGCAGAACCAGCAGCACCTGATCCCCCAGTGGGCCCTGAGACAGATC GCCGACTTCGCCCTGAAGCTGCACAAGACCCATCTGGCCAGCTTTCTGAGCGCCTTCGCCAGGCAGGAAC TGTACCTGATGGGCAGCCTGGTCCACAGCATGCTGGTGCATACCACCGAGCGGCGGGAGATCTTCATCGT GGAGACAGGCCTGTGTAGCCTGGCCGAGCTGTCCCACTTTACCCAGCTGCTGGCCCACCCTCACCACGAG TACCTGAGCGACCTGTACACCCCCTGCAGCAGCAGCGGCAGACGGGACCACAGCCTGGAACGGCTGACCA GACTGTTCCCCGATGCCACCGTGCCTGCTACAGTGCCTGCCGCCCTGTCCATCCTGTCCACCATGCAGCC CAGCACCCTGGAAACCTTCCCCGACCTGTTCTGCCTGCCCCTGGGCGAGAGCTTTAGCGCCCTGACCGTG TCCGAGCACGTGTCCTACATCGTGACCAATCAGTACCTGATCAAGGGCATCAGCTACCCCGTGTCCACCA CAGTCGTGGGCCAGAGCCTGATCATCACCCAGACCGACAGCCAGACCAAGTGCGAGCTGACCCGGAACAT GCACACCACACACAGCATCACCGTGGCCCTGAACATCAGCCTGGAAAACTGCGCTTTCTGTCAGTCTGCC CTGCTGGAATACGACGATACCCAGGGCGTGATCAACATCATGTACATGCACGACAGCGACGACGTGCTGT TCGCCCTGGACCCCTACAACGAGGTGGTGGTGTCCAGCCCCCGGACCCACTACCTGATGCTGCTGAAGAA CGGCACCGTGCTGGAAGTGACCGACGTGGTGGTGGACGCCACCGACGGCAGCGGATCTGGGTCCCACCAT CACCATCACCATTGATAATCTAGAGGCCCCTATAACTCTCTACGGCTAACCTGAATGGACTACGACATAG TCTAGTCCG CCAAGATGTGCAGAAGGCCCGACTGCGGCTTCAGCTTCAGCCCTGGACCCGTGATCCTGCT GTGGTGCTGCCTGCTGCTGCCTATCGTGTCCTCTGCCGCCGTGTCTGTGGCCCCTACAGCCGCCGAGAAG GTGCCAGCCGAGTGCCCCGAGCTGACCAGAAGATGCCTGCTGGGCGAGGTGTTCGAGGGCGACAAGTACG AGAGCTGGCTGCGGCCCCTGGTCAACGTGACCGGCAGAGATGGCCCCCTGAGCCAGCTGATCCGGTACAG ACCCGTGACCCCCGAGGCCGCCAATAGCGTGCTGCTGGACGAGGCCTTCCTGGATACCCTGGCCCTGCTG TACAACAACCCCGACCAGCTGAGAGCCCTGCTGACCCTGCTGTCCAGCGACACCGCCCCCAGATGGATGA CCGTGATGCGGGGCTACAGCGAGTGTGGAGATGGCAGCCCTGCCGTGTACACCTGCGTGGACGACCTGTG CAGAGGCTACGACCTGACCAGACTGAGCTACGGCCGGTCCATCTTCACAGAGCACGTGCTGGGCTTCGAG CTGGTGCCCCCCAGCCTGTTCAACGTGGTGGTGGCCATCCGGAACGAGGCCACCAGAACCAACAGAGCCG TGCGGCTGCCTGTGTCTACAGCCGCTGCACCTGAGGGCATCACACTGTTCTACGGCCTGTACAACGCCGT GAAAGAGTTCTGCCTCCGGCACCAGCTGGATCCCCCCCTGCTGAGACACCTGGACAAGTACTACGCCGGC CTGCCCCCAGAGCTGAAGCAGACCAGAGTGAACCTGCCCGCCCACAGCAGATATGGCCCTCAGGCCGTGG ACGCCAGATGATAACGCCGGCGGCCCCTATAACTCTCTACGGCTAACCTGAATGGACTACGACATAGTCT AGTCCGCCAAGATGAGCCCCAAGGACCTGACCCCCTTCCTGACAACCCTGTGGCTGCTCCTGGGCCATAG CAGAGTGCCTAGAGT GCGGGCCGAGGAATGCTGCGAGTTCATCAACGTGAACCACCCCCCCGAGCGGTGC TACGACTTCAAGATGTGCAACCGGTTCACCGTGGCCCTGAGATGCCCCGACGGCGAAGTGTGCTACAGCC CCGAGAAAACCGCCGAGATCCGGGGCATCGTGACCACCATGACCCACAGCCTGACCCGGCAGGTGGTGCA CAACAAGCTGACCAGCTGCAACTACAACCCCCTGTACCTGGAAGCCGACGGCCGGATCAGATGCGGCAAA GTGAACGACAAGGCCCAGTACCTGCTGGGAGCCGCCGGAAGCGTGCCCTACCGGTGGATCAACCTGGAAT ACGACAAGATCACCCGGATCGTGGGCCTGGACCAGTACCTGGAAAGCGTGAAGAAGCACAAGCGGCTGGA CGTGTGCAGAGCCAAGATGGGCTACATGCTGCAGTGATAAGGCGCGCCAACGTTACTGGCCGAAGCCGCT TGGAATAAGGCCGGTGTGCGTTTGTCTATATGTTATTTTCCACCATATTGCCGTCTTTTGGCAATGTGAG GGCCCGGAAACCTGGCCCTGTCTTCTTGACGAGCATTCCTAGGGGTCTTTCCCCTCTCGCCAAAGGAATG CAAGGTCTGTTGAATGTCGTGAAGGAAGCAGTTCCTCTGGAAGCTTCTTGAAGACAAACAACGTCTGTAG CGACCCTTTGCAGGCAGCGGAACCCCCCACCTGGCGACAGGTGCCTCTGCGGCCAAAAGCCACGTGTATA AGATACACCTGCAAAGGCGGCACAACCCCAGTGCCACGTTGTGAGTTGGATAGTTGTGGAAAGAGTCAAA TGGCTCTCCTCAAGCGTATTCAACAAGGGGCTGAAGGATGCCCAGAAGGTACCCCATTGTATGGGATCTG ATCTGGGGCCTCGGTGCACATGCTTTACATGTGTTTAGTCGAGGTTAAAAAAACGTCTAGGCCCCCCGAA CCACGGGGACGTGGTTTTCCT TTGAAAAACACGATAATATGCTGCGGCTGCTGCTGAGACACCACTTCCA CTGCCTGCTGCTGTGTGCCGTGTGGGCCACCCCTTGTCTGGCCAGCCCTTGGAGCACCCTGACCGCCAAC CAGAACCCTAGCCCCCCTTGGTCCAAGCTGACCTACAGCAAGCCCCACGACGCCGCCACCTTCTACTGCC CCTTTCTGTACCCCAGCCCTCCCAGAAGCCCCCTGCAGTTCAGCGGCTTCCAGAGAGTGTCCACCGGCCC TGAGTGCCGGAACGAGACACTGTACCTGCTGTACAACCGGGAGGGCCAGACACTGGTGGAGCGGAGCAGC ACCTGGGTGAAAAAAGTGATCTGGTATCTGAGCGGCCGGAACCAGACCATCCTGCAGCGGATGCCCAGAA CCGCCAGCAAGCCCAGCGACGGCAACGTGCAGATCAGCGTGGAGGACGCCAAAATCTTCGGAGCCCACAT GGTGCCCAAGCAGACCAAGCTGCTGAGATTCGTGGTCAACGACGGCACCAGATATCAGATGTGCGTGATG AAGCTGGAAAGCTGGGCCCACGTGTTCCGGGACTACTCCGTGAGCTTCCAGGTCCGGCTGACCTTCACCG AGGCCAACAACCAGACCTACACCTTCTGCACCCACCCCAACCTGATCGTGTGATAAGTACCTTTGTACGC CTGTTTTATACCCCCTCCCTGATTTGCAACTTAGAAGCAACGCAAACCAGATCAATAGTAGGTGTGACAT ACCAGTCGCATCTTGATCAAGCACTTCTGTATCCCCGGACCGAGTATCAATAGACTGTGCACACGGTTGA AGGAGAAAACGTCCGTTACCCGGCTAACTACTTCGAGAAGCCTAGTAACGCCATTGAAGTTGCAGAGTGT TTCGCTCAGCACTCCCCCCGTGTAGATCAGGTCGATGAGTCACCGCATTCCCCACGGGCGACCGTGGCGG TGGCTGCGTTGGCGGCCTGCCTATGGG GTAACCCATAGGACGCTCTAATACGGACATGGCGTGAAGAGTC TATTGAGCTAGTTAGTAGTCCTCCGGCCCCTGAATGCGGCTAATCCTAACTGCGGAGCACATACCCTTAA TCCAAAGGGCAGTGTGTCGTAACGGGCAACTCTGCAGCGGAACCGACTACTTTGGGTGTCCGTGTTTCTT TTTATTCTTGTATTGGCTGCTTATGGTGACAATTAAAGAATTGTTACCATATAGCTATTGGATTGGCCAT CCAGTGTCAAACAGAGCTATTGTATATCTCTTTGTTGGATTCACACCTCTCACTCTTGAAACGTTACACA CCCTCAATTACATTATACTGCTGAACACGAAGCGCATATGCGGCTGTGCAGAGTGTGGCTGTCCGTGTGC CTGTGTGCCGTGGTGCTGGGCCAGTGCCAGAGAGAGACAGCCGAGAAGAACGACTACTACCGGGTGCCCC ACTACTGGGATGCCTGCAGCAGAGCCCTGCCCGACCAGACCCGGTACAAATACGTGGAGCAGCTCGTGGA CCTGACCCTGAACTACCACTACGACGCCAGCCACGGCCTGGACAACTTCGACGTGCTGAAGCGGATCAAC GTGACCGAGGTGTCCCTGCTGATCAGCGACTTCCGGCGGCAGAACAGAAGAGGCGGCACCAACAAGCGGA CCACCTTCAACGCCGCTGGCTCTCTGGCCCCTCACGCCAGATCCCTGGAATTCAGCGTGCGGCTGTTCGC CAACTGATAACGTTGCATCCTGCAGGATACAGCAGCAATTGGCAAGCTGCTTACATAGAACTCGCGGCGA TTGGCATGCCGCCTTAAAATTTTTATTTTATTTTTCTTTTCTTTTCCGAATCGGATTTTGTTTTTAATAT TTCAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAGGGTCGGCATGGCATCTCCACCTCCTCGCGGT CCGACCTGGGCATCCGAAGGAGGACGCACGTCC ACTCGGATGGCTAAGGGAGAGCCACGTTTAAACGCTA GAGCAAGACGTTTCCCGTTGAATATGGCTCATAACACCCCTTGTATTACTGTTTATGTAAGCAGACAGTT TTATTGTTCATGATGATATATTTTTATCTTGTGCAATGTAACATCAGAGATTTTGAGACACAACGTGGCT TTGTTGAATAAATCGAACTTTTGCTGAGTTGAAGGATCAGATCACGCATCTTCCCGACAACGCAGACCGT TCCGTGGCAAAGCAAAAGTTCAAAATCACCAACTGGTCCACCTACAACAAAGCTCTCATCAACCGTGGCT CCCTCACTTTCTGGCTGGATGATGGGGCGATTCAGGCCTGGTATGAGTCAGCAACACCTTCTTCACGAGG CAGACCTCAGCGCTAGCGGAGTGTATACTGGCTTACTATGTTGGCACTGATGAGGGTGTCAGTGAAGTGC TTCATGTGGCAGGAGAAAAAAGGCTGCACCGGTGCGTCAGCAGAATATGTGATACAGGATATATTCCGCT TCCTCGCTCACTGACTCGCTACGCTCGGTCGTTCGACTGCGGCGAGCGGAAATGGCTTACGAACGGGGCG GAGATTTCCTGGAAGATGCCAGGAAGATACTTAACAGGGAAGTGAGAGGGCCGCGGCAAAGCCGTTTTTC CATAGGCTCCGCCCCCCTGACAAGCATCACGAAATCTGACGCTCAAATCAGTGGTGGCGAAACCCGACAG GACTATAAAGATACCAGGCGTTTCCCCTGGCGGCTCCCTCGTGCGCTCTCCTGTTCCTGCCTTTCGGTTT ACCGGTGTCATTCCGCTGTTATGGCCGCGTTTGTCTCATTCCACGCCTGACACTCAGTTCCGGGTAGGCA GTTCGCTCCAAGCTGGACTGTATGCACGAACCCCCCGTTCAGTCCGACCGCTGCGCCTTATCCGGTAACT ATCGTCTTGAGTCCAACCCGGAAAGACATGCAAAAGCAC CACTGGCAGCAGCCACTGGTAATTGATTTAG AGGAGTTAGTCTTGAAGTCATGCGCCGGTTAAGGCTAAACTGAAAGGACAAGTTTTGGTGACTGCGCTCC TCCAAGCCAGTTACCTCGGTTCAAAGAGTTGGTAGCTCAGAGAACCTTCGAAAAACCGCCCTGCAAGGCG GTTTTTTCGTTTTCAGAGCAAGAGATTACGCGCAGACCAAAACGATCTCAAGAAGATCATCTTATTAAGG GGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTT CACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCT GACAGTTATTAGAAAAATTCATCCAGCAGACGATAAAACGCAATACGCTGGCTATCCGGTGCCGCAATGC CATACAGCACCAGAAAACGATCCGCCCATTCGCCGCCCAGTTCTTCCGCAATATCACGGGTGGCCAGCGC AATATCCTGATAACGATCCGCCACGCCCAGACGGCCGCAATCAATAAAGCCGCTAAAACGGCCATTTTCC ACCATAATGTTCGGCAGGCACGCATCACCATGGGTCACCACCAGATCTTCGCCATCCGGCATGCTCGCTT TCAGACGCGCAAACAGCTCTGCCGGTGCCAGGCCCTGATGTTCTTCATCCAGATCATCCTGATCCACCAG GCCCGCTTCCATACGGGTACGCGCACGTTCAATACGATGTTTCGCCTGATGATCAAACGGACAGGTCGCC GGGTCCAGGGTATGCAGACGACGCATGGCATCCGCCATAATGCTCACTTTTTCTGCCGGCGCCAGATGGC TAGACAGCAGATCCTGACCCGGCACTTCGCCCAGCAGCAGCCAATCACGGCCCGCTTCGGTCACCACATC CAGCACCGCCGCACACGGAACACCGGTGGTGGCCAGCCAGCTCAG ACGCGCCGCTTCATCCTGCAGCTCG TTCAGCGCACCGCTCAGATCGGTTTTCACAAACAGCACCGGACGACCCTGCGCGCTCAGACGAAACACCG CCGCATCAGAGCAGCCAATGGTCTGCTGCGCCCAATCATAGCCAAACAGACGTTCCACCCACGCTGCCGG GCTACCCGCATGCAGGCCATCCTGTTCAATCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAG GGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCA CATTTCCCCGAAAAGTGCCACCTAAATTGTAAGCGTTAATATTTTGTTAAAATTCGCGTTAAATTTTTGT TAAATCAGCTCATTTTTTAACCAATAGGCCGAAATCGGCAAAATCCCTTATAAATCAAAAGAATAGACCG AGATAGGGTTGAGTGGCCGCTACAGGGCGCTCCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGC GTTTCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTT GGGTAACGCCAGGGTTTTCCCAGTCACACGCGTAATACGACTCACTATAG VZV gB MFVTAVVSVSPSSFYESLQVEPTQSEDITRSAHLGDGDEIREAIHKSQDAETKPTFYVC PPPTGSTIVRLEPPRTCPDYHLGKNFTEGIAVVYKENIAAYKFKATVYYKDVIVSTAWA GSSYTQITNRYADRVPIPVSEITDTIDKFGKCSSKATYVRNNHKVEAFNEDKNPQDMPL IASKYNSVGSKAWHTTNDTYMVAGTPGTYRTGTSVNCIIEEVEARSIFPYDSFGLSTGD IIYMSPFFGLRDGAYREHSNYAMDRFHQFEGYRQRDLDTRALLEPAARNFLVTPHLTVG WNWKPKRTEVCSLVKWREVEDVVRDEYAHNFRFTMKTLSTTFISETNE FNLNQIHLSQC VKEEARAIINRIYTTRYNSSHVRTGDIQTYLARGGFVVVFQPLLSNSLARLYLQELVRE NTNHSPQKHPTRNTRSRRSVPVELRANRTITTTSSVEFAMLQFTYDHIQEHVNEMLARI SSSWCQLQNRERALWSGLFPINPSALASTILDQRVKARILGDVISVSNCPELGSDTRII LQNSMRVSGSTTRCYSRPLISIVSLNGSGTVEGQLGTDNELIMSRDLLEPCVANHKRYF LFGHHYVYYEDYRYVREIAVHDVGMISTYVDLNLTLLKDREFMPLQVYTRDELRDTGLL DYSEIQRRNQMHSLRFYDIDKVVQYDSGTAIMQGMAQFFQGLGTAGQAVGHVVLGATGA LLSTVHGFTTFLSNPFGALAVGLLVLAGLVAAFFAYRYVLKLKTSPMKALYPLTTKGLK QLPEGMDPFAEKPNATDTPIEEIGDSQNTEPSVNSGFDPDKFREAQEMIKYMTLVSAAE RQESKARKKNKTSALLTSRLTGLALRNRRGYSRVRTENVTGV VZV gH MFALVLAVVILPLWTTANKSYVTPTPATRSIGHMSALLREYSDRNMSLKLEAFYPTGFD EELIKSLHWGNDRKHVFLVIVKVNPTTHEGDVGLVIFPKYLLSPYHFKAEHRAPFPAGR FGFLSHPVTPDVSFFDSSFAPYLTTQHLVAFTTFPPNPLVWHLERAETAATAERPFGVS LLPARPTVPKNTILEHKAHFATWDALARHTFFSAEAIITNSTLRIHVPLFGSVWPIRYW ATGSVLLTSDSGRVEVNIGVGFMSSLISLSSGLPIELIVVPHTVKLNAVTSDTTWFQLN PPGPDPGPSYRVYLLGRGLDMNFSKHATVDICAYPEESLDYRYHLSMAHTEALRMTTKA DQHDINEESYYHIAARIATSIFALSEMGRTTEYFLLDEIVDVQYQLKFLNYILMRIGAG AHPNTISGTSDLIFADPSQLHDELSLLFGQVKPANVDY FISYDEARDQLKTAYALSRGQ DHVNALSLARRVIMSIYKGLLVKQNLNATERQALFFASMILLNFREGLENSSRVLDGRT TLLLMTSMCTAAHATQAALNIQEGLAYLNPSKHMFTIPNVYSPCMGSLRTDLTEEIHVM NLLSAIPTRPGLNEVLHTQLDESEIFDAAFKTMMIFTTWTAKDLHILHTHVPEVFTCQD AAARNGEYVLILPAVQGHSYVITRNKPQRGLVYSLADVDVYNPISVVYLSKDTCVSEHG VIETVALPHPDNLKECLYCGSVFLRYLTTGAIMDIIIIDSKDTERQLAAMGNSTIPPFN PDMHGDDSKAVLLFPNGTVVTLLGFERRQAIRMSGQYLGASLGGAFLAVVGFGIIGWML CGNSRLREYNKIPLT VZV gL MASHKWLLQMIVFLKTITIAYCLHLQDDTPLFFGAKPLSDVSLIITEPCVSSVYEAWDY AAPPVSNLSEALSGIVVKTKCPVPEVILWFKDKQMAYWTNPYVTLKGLTQSVGEEHKSG DIRDALLDALSGVWVDSTPSSTNIPENGCVWGADRLFQRVCQ VZV gI MFLIQCLISAVIFYIQVTNALIFKGDHVSLQVNSSLTSILIPMQNDNYTEIKGQLVFIG EQLPTGTNYSGTLELLYADTVAFCFRSVQVIRYDGCPRIRTSAFISCRYKHSWHYGNST DRISTEPDAGVMLKITKPGINDAGVYVLLVRLDHSRSTDGFILGVNVYTAGSHHNIHGV IYTSPSLQNGYSTRALFQQARLCDLPATPKGSGTSLFQHMLDLRAGKSLEDNPWLHEDV VTTETKSVVKEGIENHVYPTDMSTLPEKSLNDPPENLLIIIPIVASVMILTAMVIVIVI SVKRRRIKKHPIYRPNTKTRRGIQNATPESDVMLEAAIAQLATIREESPPHSVVNPFVK VZV gE MGTVNKPVVGVLMGFGIITGTLRITNPVRASVLRYDDFHIDEDKLDTNSVYEPYYHSD H AESSWVNRGESSRKAYDHNSPYIWPRNDYDGFLENAHEHHGVYNQGRGIDSGERLMQPT QMSAQEDLGDDTGIHVIPTLNGDDRHKIVNVDQRQYGDVFKGDLNPKPQGQRLIEVSVE ENHPFTLRAPIQRIYGVRYTETWSFLPSLTCTGDAAPAIQHICLKHTTCFQDVVVDVDC AENTKEDQLAEISYRFQGKKEADQPWIVVNTSTLFDELELDPPEIEPGVLKVLRTEKQY LGVYIWNMRGSDGTSTYATFLVTWKGDEKTRNPTPAVTPQPRGAEFHMWNYHSHVFSVG DTFSLAMHLQYKIHEAPFDLLLEWLYVPIDPTCQPMRLYSTCLYHPNAPQCLSHMNSGC TFTSPHLAQRVASTVYQNCEHADNYTAYCLGISHMEPSFGLILHDGGTTLKFVDTPESL SGLYVFVVYFNGHVEAVAYTVVSTVDHFVNAIEERGFPPTAGQPPATTKPKEITPVNPG TSPLLRYAAWTGGLAAVVLLCLVIFLICTAKRMRVKAYRVDKSPYNQSMYYAGLPVDDF EDSESTDTEEEFGNAIGGSHGGSSYTVYIDKTR VEERep VZV. SGPgB 1-ataggcggcgcatgagagaagcccagaccaattacctacccaaaatggagaaagttcacgttga catcgaggaagacagcccattcctcagagctttgcagcggagcttcccgcagtttgaggtagaa gccaagcaggtcactgataatgaccatgctaatgccagagcgttttcgcatctggcttcaaaac tgatcgaaacggaggtggacccatccgacacgatccttgacattggaagtgcgcccgcccgcag aatgtattctaagcacaagtatcattgtatctgtccgatgagatgtgcggaagatccggacaga ttgtataagtatgcaactaagctgaagaaaaactgtaaggaaataactgataaggaattggaca agaaaatgaaggagctcgccgccgtcatgagcgaccctgacctggaaactgagactatgtgcct ccacgacgacgagtcgtgtcgctacgaagggcaagtcgctgtttaccaggatgtatacgcggtt gacggaccgacaagtctctatcaccaagccaataagggagttagagtcgcctactggataggct ttgacaccaccccttttatgtttaagaacttggctggagcatatccatcatactctaccaactg ggccgacgaaaccgtgttaacggctcgtaacataggcctatgcagctctgacgttatggagcgg tcacgtagagggatgtccattcttagaaagaagtatttgaaaccatccaacaatgttctattct ctgttggctcgaccatctaccacgagaagagggacttactgaggagctggcacctgccgtctgt atttcacttacgtggcaagcaaaattacacatgtcggtgtgagactatagttagttgcgacggg tacgtcgttaaaagaatagctatcagtccaggcctgtatgggaagccttcaggctatgctgcta cgatgcaccgcgaggga ttcttgtgctgcaaagtgacagacacattgaacggggagagggtctc ttttcccgtgtgcacgtatgtgccagctacattgtgtgaccaaatgactggcatactggcaaca gatgtcagtgcggacgacgcgcaaaaactgctggttgggctcaaccagcgtatagtcgtcaacg gtcgcacccagagaaacaccaataccatgaaaaattaccttttgcccgtagtggcccaggcatt tgctaggtgggcaaaggaatataaggaagatcaagaagatgaaaggccactaggactacgagat agacagttagtcatggggtgttgttgggcttttagaaggcacaagataacatctatttataagc gcccggatacccaaaccatcatcaaagtgaacagcgatttccactcattcgtgctgcccaggat aggcagtaacacattggagatcgggctgagaacaagaatcaggaaaatgttagaggagcacaag gagccgtcacctctcattaccgccgaggacgtacaagaagctaagtgcgcagccgatgaggcta aggaggtgcgtgaagccgaggagttgcgcgcagctctaccacctttggcagctgatgttgagga gcccactctggaagccgatgtagacttgatgttacaagaggctggggccggctcagtggagaca cctcgtggcttgataaaggttaccagctacgatggcgaggacaagatcggctcttacgctgtgc tttctccgcaggctgtactcaagagtgaaaaattatcttgcatccaccctctcgctgaacaagt catagtgataacacactctggccgaaaagggcgttatgccgtggaaccataccatggtaaagta gtggtgccagagggacatgcaatacccgtccaggactttcaagctctgagtgaaagtgccacca ttgtgtacaacgaacgtgagttcgtaaacaggtacctgcacc atattgccacacatggaggagc gctgaacactgatgaagaatattacaaaactgtcaagcccagcgagcacgacggcgaatacctg tacgacatcgacaggaaacagtgcgtcaagaaagaactagtcactgggctagggctcacaggcg agctggtggatcctcccttccatgaattcgcctacgagagtctgagaacacgaccagccgctcc ttaccaagtaccaaccataggggtgtatggcgtgccaggatcaggcaagtctggcatcattaaa agcgcagtcaccaaaaaagatctagtggtgagcgccaagaaagaaaactgtgcagaaattataa gggacgtcaagaaaatgaaagggctggacgtcaatgccagaactgtggactcagtgctcttgaa tggatgcaaacaccccgtagagaccctgtatattgacgaagcttttgcttgtcatgcaggtact ctcagagcgctcatagccattataagacctaaaaaggcagtgctctgcggggatcccaaacagt gcggtttttttaacatgatgtgcctgaaagtgcattttaaccacgagatttgcacacaagtctt ccacaaaagcatctctcgccgttgcactaaatctgtgacttcggtcgtctcaaccttgttttac gacaaaaaaatgagaacgacgaatccgaaagagactaagattgtgattgacactaccggcagta ccaaacctaagcaggacgatctcattctcacttgtttcagagggtgggtgaagcagttgcaaat agattacaaaggcaacgaaataatgacggcagctgcctctcaagggctgacccgtaaaggtgtg tatgccgttcggtacaaggtgaatgaaaatcctctgtacgcacccacctcagaacatgtgaacg aa tcctactgacccgcacggaggaccgcatcgtgtggaaaacactagccggcgacccatggataaa cactgactgccaagtaccctgggaatttcactgccacgatagaggagtggcaagcagagcat gatgccatcatgaggcacatcttggagagaccggaccctaccgacgtcttccagaataaggcaa acgtgtgttgggccaaggctttagtgccggtgctgaagaccgctggcatagacatgaccactga acaatggaacactgtggattattttgaaacggacaaagctcactcagcagagatagtattgaac caactatgcgtgaggttctttggactcgatctggactccggtctattttctgcacccactgttc cgttatccattaggaataatcactgggataactccccgtcgcctaacatgtacgggctgaataa agaagtggtccgtcagctctctcgcaggtacccacaactgcctcgggcagttgccactggaaga gtctatgacatgaacactggtacactgcgcaattatgatccgcgcataaacctagtacctgtaa acagaagactgcctcatgctttagtcctccaccataatgaacacccacagagtgacttttcttc attcgtcagcaaattgaagggcagaactgtcctggtggtcggggaaaagttgtccgtcccaggc aaaatggttgactggttgtcagaccggcctgaggctaccttcagagctcggctggatttaggca tcccaggtgatgtgcccaaatatgacataatatttgttaatgtgaggaccccatataaatacca tcactatcagcagtgtgaagaccatgccattaagcttagcatgttgaccaagaaagcttgtctg catctgaatcccggcggaacctgtgtcagcataggttatggttacgctgacagggccagcgaaa gcatcattggtgctatagcgcggcagttcaagttttcccgggtatgcaaaccgaaatcctcact tgaagagacggaagttctgtttgtatt cattgggtacgatcgcaaggcccgtacgcacaatcct tacaagctttcatcaaccttgaccaacatttatacaggttccagactccacgaagccggatgtg caccctcatatcatgtggtgcgaggggatattgccacggccaccgaaggagtgattataaatgc tgctaacagcaaaggacaacctggcggaggggtgtgcggagcgctgtataagaaattcccggaa agcttcgatttacagccgatcgaagtaggaaaagcgcgactggtcaaaggtgcagctaaacata tcattcatgccgtaggaccaaacttcaacaaagtttcggaggttgaaggtgacaaacagttggc agaggcttatgagtccatcgctaagattgtcaacgataacaattacaagtcagtagcgattcca ctgttgtccaccggcatcttttccgggaacaaagatcgactaacccaatcattgaaccatttgc tgacagctttagacaccactgatgcagatgtagccatatactgcagggacaagaaatgggaaat gactctcaaggaagcagtggctaggagagaagcagtggaggagatatgcatatccgacgactct tcagtgacagaacctgatgcagagctggtgagggtgcatccgaagagttctttggctggaagga agggctacagcacaagcgatggcaaaactttctcatatttggaagggaccaagtttcaccaggc ggccaaggatatagcagaaattaatgccatgtggcccgttgcaacggaggccaatgagcaggta tgcatgtatatcctcggagaaagcatgagcagtattaggtcgaaatgccccgtcgaagagtcgg aagcctccacaccacctagcacgctgccttgcttgtgcatccatgccatgactccagaaagagt acagcgcctaaaagcctcacgtccagaacaaattactgtgtgctcatccttt ccattgccgaag tatagaatcactggtgtgcagaagatccaatgctcccagcctatattgttctcaccgaaagtgc ctgcgtatattcatccaaggaagtatctcgtggaaacaccaccggtagacgagactccggagcc atcggcagagaaccaatccacagaggggacacctgaacaaccaccacttataaccgaggatgag accaggactagaacgcctgagccgatcatcatcgaagaggaagaagaggatagcataagtttgc tgtcagatggcccgacccaccaggtgctgcaagtcgaggcagacattcacgggccgccctctgt atctagctcatcctggtccattcctcatgcatccgactttgatgtggacagtttatccatactt gacaccctggagggagctagcgtgaccagcggggcaacgtcagccgagactaactcttacttcg caaagagtatggagtttctggcgcgaccggtgcctgcgcctcgaacagtattcaggaaccctcc acatcccgctccgcgcacaagaacaccgtcacttgcacccagcagggcctgctcgagaaccagc ctagtttccaccccgccaggcgtgaatagggtgatcactagagaggagctcgaggcgcttaccc cgtcacgcactcctagcaggtcggtctcgagaaccagcctggtctccaacccgccaggcgtaaa tagggtgattacaagagaggagtttgaggcgttcgtagcacaacaacaatgacggtttgatgcg ggtgcatacatcttttcctccgacaccggtcaagggcatttacaacaaaaatcagtaaggcaaa cggtgctatccgaagtggtgttggagaggaccgaattggagatttcgtatgccccgcgcctcga ccaagaaaaagaagaattactacgcaagaaattacagttaaatcccacacctgctaacagaagc agataccagtcc aggaaggtggagaacatgaaagccataacagctagacgtattctgcaaggcc tagggcattatttgaaggcagaaggaaaagtggagtgctaccgaaccctgcatcctgttccttt gtattcatctagtgtgaaccgtgccttttcaagccccaaggtcgcagtggaagcctgtaacgcc atgttgaaagagaactttccgactgtggcttcttactgtattattccagagtacgatgcctatt tggacatggttgacggagcttcatgctgcttagacactgccagtttttgccctgcaaagctgcg cagctttccaaagaaacactcctatttggaacccacaatacgatcggcagtgccttcagcgatc cagaacacgctccagaacgtcctggcagctgccacaaaaagaaattgcaatgtcacgcaaatga gagaattgcccgtattggattcggcggcctttaatgtggaatgcttcaagaaatatgcgtgtaa taatgaatattgggaaacgtttaaagaaaaccccatcaggcttactgaagaaaacgtggtaaat tacattaccaaattaaaaggaccaaaagctgctgctctttttgcgaagacacataatttgaata tgttgcaggacataccaatggacaggtttgtaatggacttaaagagagacgtgaaagtgactcc aggaacaaaacatactgaagaacggcccaaggtacaggtgatccaggctgccgatccgctagca acagcgtatctgtgcggaatccaccgagagctggttaggagattaaatgcggtcctgcttccga acattcatacactgtttgatatgtcggctgaagactttgacgctattatagccgagcacttcca gcctggggattgtgttctggaaactgacatcgcgtcgtttgataaaagtgaggacgacgccatg gctctgaccgcgttaatgattctggaagacttaggtg tggacgcagagctgttgacgctgattg aggcggctttcggcgaaatttcatcaatacatttgcccactaaaactaaatttaaattcggagc catgatgaaatctggaatgttcctcacactgtttgtgaacacagtcattaacattgtaatcgca agcagagtgttgagagaacggctaaccggatcaccatgtgcagcattcattggagatgacaata tcgtgaaaggagtcaaatcggacaaattaatggcagacaggtgcgccacctggttgaatatgga agtcaagattatagatgctgtggtgggcgagaaagcgccttatttctgtggagggtttattttg tgtgactccgtgaccggcacagcgtgccgtgtggcagaccccctaaaaaggctgtttaagcttg gcaaacctctggcagcagacgatgaacatgatgatgacaggagaagggcattgcatgaagagtc aacacgctggaaccgagtgggtattctttcagagctgtgcaaggcagtagaatcaaggtatgaa accgtaggaacttccatcatagttatggccatgactactctagctagcagtgttaaatcattca gctacctgagaggggcccctataactctctacggctaacctgaatggactacgacatagtctag tcgagtctagtcgacgccaccatgttcgtgaccgccgtggtgtccgtgtcccccagcagctttt acgagagcctgcaggtcgagcccacccagagcgaggacatcacaagatctgcccacctgggcga cggcgacgagatcagagaggccatccacaagagccaggacgccgagacaaagcccaccttctac gtgtgccccccacctaccggctctacaattgtgcggctggaaccccccagaacctgccctgatt accacctgggcaagaacttcaccgagggaattgccgtggtgtacaaagagaatatcgccgcc rt caagttcaaggccaccgtgtactacaaggacgtgatcgtgtccaccgcctgggccggcagcagc tacacccagatcaccaacagatacgccgaccgggtgcccatccccgtgtctgagatcaccgaca ccatcgacaagttcggcaagtgcagcagcaaggccacctacgtgcggaacaaccacaaggtgga agccttcaacgaggacaagaacccccaggacatgcccctgatcgccagcaagtacaacagcgtg ggctccaaggcctggcacaccaccaacgacacctacatggtggccggcacccccggcacataca gaacaggcaccagcgtgaactgcatcatcgaggaagtggaagcccggtccatcttcccatacga cagcttcggcctgagcaccggcgacattatctacatgagccctttcttcggcctgcgggacggc gcctacagagagcacagcaactacgccatggaccggttccaccagttcgagggctacagacagc gggacctggacacaagagccctgctggaacctgccgccagaaacttcctggtcacccctcacct gaccgtgggctggaactggaagcccaagcggaccgaagtgtgcagcctggtcaagtggcgcgag gtggaagatgtcgtgcgggatgagtacgcccacaacttccggttcaccatgaagaccctgagca ccaccttcatcagcgagacaaacgagttcaacctgaaccagatccacctgagccagtgcgtgaa agaggaagccagagccatcatcaaccggatctacaccacccggtacaacagcagccacgtgcgg accggcgatatccagacctatctggctagaggcggcttcgtggtggtgtttcagcccctgctga gcaacagcctggctagactgtacctgcaggaactcgtcagagagaacaccaaccacagccccca gaagcaccccacccggaatacc agatccagacgcagcgtgcccgtggaactgagagccaaccgg accatcaccaccaccagcagcgtggaattcgccatgctgcagttcacctacgaccacatccagg aacacgtgaacgagatgctggcccggatcagcagcagttggtgccagctgcagaatcgggaaag ggccctgtggtccggcctgttccccatcaatccaagcgccctggccagcaccatcctggaccag agagtgaaggccagaatcctgggggacgtgatcagcgtgtccaactgtcctgagctgggcagcg acacccggatcatcctgcagaacagcatgcgggtgtccggcagcaccaccagatgctacagcag acccctgatcagcatcgtgtccctgaacggcagcggcacagtggaaggccagctgggcaccgat aacgagctgatcatgagccgggacctgctcgaaccctgcgtggccaatcacaagcggtactttc tgttcggccaccactacgtgtactatgaggactacagatacgtgcgcgagatcgccgtgcacga cgtgggcatgatcagcacctacgtggacctgaacctgaccctgctgaaggaccgcgagttcatg ccactgcaggtctacacccgggacgagctgagagataccggcctgctggactacagcgagatcc agcggcggaaccagatgcactccctgcggttctacgacatcgacaaggtggtgcagtacgacag cggcaccgccatcatgcagggcatggcccagttctttcagggcctgggaacagccggacaggcc gtgggacatgtggtgctgggagctacaggcgccctgctgtctaccgtgcacggcttcaccacct ttctgagcaaccccttcggagccctggctgtgggactgctggtcctggctggactggtggccgc cttctttgcctaccgctacgtgctgaagctgaaaaccagccccatga aggccctgtaccccctg accaccaagggcctgaagcagctgcctgagggcatggaccccttcgccgagaagcccaatgcca ccgacacccccatcgaggaaatcggcgacagccagaacaccgagccctccgtgaacagcggctt cgaccccgacaagtttcgcgaggcccaggaaatgatcaagtacatgaccctggtgtctgctgcc gagcggcaggaaagcaaggcccggaagaagaacaagacctccgccctgctgaccagcagactga caggactggccctgcggaacagacggggctatagcagagtgcggaccgagaatgtgaccggcgt gtaatctagacgcggccgcatacagcagcaattggcaagctgcttacatagaactcgcggcgat tggcatgccgccttaaaatttttattttatttttcttttcttttccgaatcggattttgttttt aatatttcaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaagggtcggcatggcatctccac ctcctcgcggtccgacctgggcatccgaaggaggacgcacgtccactcggatggctaagggaga gccacgtttaaaccagctccaattcgccctatagtgagtcgtattacgcgcgctcactggccgt cgttttacaacgtcgtgactgggaaaaccctggcgttacccaacttaatcgccttgcagcacat ccccctttcgccagctggcgtaatagcgaagaggcccgcaccgatcgcccttcccaacagttgc gcagcctgaatggcgaatgggacgcgccctgtagcggcgcattaagcgcggcgggtgtggtggt tacgcgcagcgtgaccgctacacttgccagcgccctagcgcccgctcctttcgctttcttccct tcctttctcgccacgttcgccggctttccccgtcaagctctaaatcgggggctccctttagggt tccgatt tagtgctttacggcacctcgaccccaaaaaacttgattagggtgatggttcacgtag tgggccatcgccctgatagacggtttttcgccctttgacgttggagtccacgttctttaatagt ggactcttgttccaaactggaacaacactcaaccctatctcggtctattcttttgatttataag ggattttgccgatttcggcctattggttaaaaaatgagctgatttaacaaaaatttaacgcgaa ttttaacaaaatattaacgcttacaatttaggtggcacttttcggggaaatgtgcgcggaaccc ctatttgtttatttttctaaatacattcaaatatgtatccgctcatgagacaataaccctgata aatgcttcaataatattgaaaaaggaagagtatgagtattcaacatttccgtgtcgcccttatt cccttttttgcggcattttgccttcctgtttttgctcacccagaaacgctggtgaaagtaaaag atgctgaagatcagttgggtgcacgagtgggttacatcgaactggatctcaacagcggtaagat ccttgagagttttcgccccgaagaacgttttccaatgatgagcacttttaaagttctgctatgt ggcgcggtattatcccgtattgacgccgggcaagagcaactcggtcgccgcatacactattctc agaatgacttggttgagtactcaccagtcacagaaaagcatcttacggatggcatgacagtaag agaattatgcagtgctgccataaccatgagtgataacactgcggccaacttacttctgacaacg atcggaggaccgaaggagctaaccgcttttttgcacaacatgggggatcatgtaactcgccttg atcgttgggaaccggagctgaatgaagccataccaaacgacgagcgtgacaccacgatgcctgt agcaatggcaacaacgttgcgcaaactattaa ctggcgaactacttactctagcttcccggcaa caattaatagactggatggaggcggataaagttgcaggaccacttctgcgctcggcccttccgg ctggctggtttattgctgataaatctggagccggtgagcgtgggtctcgcggtatcattgcagc actggggccagatggtaagccctcccgtatcgtagttatctacacgacggggagtcaggcaact atggatgaacgaaatagacagatcgctgagataggtgcctcactgattaagcattggtaactgt cagaccaagtttactcatatatactttagattgatttaaaacttcatttttaatttaaaaggat ctaggtgaagatcctttttgataatctcatgaccaaaatcccttaacgtgagttttcgttccac tgagcgtcagaccccgtagaaaagatcaaaggatcttcttgagatcctttttttctgcgcgtaa tctgctgcttgcaaacaaaaaaaccaccgctaccagcggtggtttgtttgccggatcaagagct accaactctttttccgaaggtaactggcttcagcagagcgcagataccaaatactgttcttcta gtgtagccgtagttaggccaccacttcaagaactctgtagcaccgcctacatacctcgctctgc taatcctgttaccagtggctgctgccagtggcgataagtcgtgtcttaccgggttggactcaag acgatagttaccggataaggcgcagcggtcgggctgaacggggggttcgtgcacacagcccagc ttggagcgaacgacctacaccgaactgagatacctacagcgtgagctatgagaaagcgccacgc ttcccgaagggagaaaggcggacaggtatccggtaagcggcagggtcggaacaggagagcgcac gagggagcttccagggggaaacgcctggtatctttatagtcctgtcgggtttcgcca cctctga cttgagcgtcgatttttgtgatgctcgtcaggggggcggagcctatggaaaaacgccagcaacg cggcctttttacggttcctggccttttgctggccttttgctcacatgttctttcctgcgttatc ccctgattctgtggataaccgtattaccgcctttgagtgagctgataccgctcgccgcagccga acgaccgagcgcagcgagtcagtgagcgaggaagcggaagagcgcccaatacgcaaaccgcctc tccccgcgcgttggccgattcattaatgcagctggcacgacaggtttcccgactggaaagcggg cagtgagcgcaacgcaattaatgtgagttagctcactcattaggcaccccaggctttacacttt atgctcccggctcgtatgttgtgtggaattgtgagcggataacaatttcacacaggaaacagct atgaccatgattacgccaagcgcgcaattaaccctcactaaagggaacaaaagctgggtaccgg gcccacgcgtaatacgactcactatag_13339 VZV VEERep. SGPgH 1_ataggcggcgcatgagagaagcccagaccaattacctacccaaaatggagaaagttcacgttga catcgaggaagacagcccattcctcagagctttgcagcggagcttcccgcagtttgaggtagaa gccaagcaggtcactgataatgaccatgctaatgccagagcgttttcgcatctggcttcaaaac tgatcgaaacggaggtggacccatccgacacgatccttgacattggaagtgcgcccgcccgcag aatgtattctaagcacaagtatcattgtatctgtccgatgagatgtgcggaagatccggacaga ttgtataagtatgcaactaagctgaagaaaaactgtaaggaaataactgataaggaattggaca agaaaatgaaggagctcgccgccgtcatgagcgaccctgacctggaaactgagactatgtgcct ccacgacgacgagtcgtgtcgctacgaagggcaagtcgctgtttaccaggatgtatacgcggtt gacggaccgacaagtctctatcaccaagccaataagggagttagagtcgcctactggataggct ttgacaccaccccttttatgtttaagaacttggctggagcatatccatcatactctaccaactg ggccgacgaaaccgtgttaacggctcgtaacataggcctatgcagctctgacgttatggagcgg tcacgtagagggatgtccattcttagaaagaagtatttgaaaccatccaacaatgttctattct ctgttggctcgaccatctaccacgagaagagggacttactgaggagctggcacctgccgtctgt atttcacttacgtggcaagcaaaattacacatgtcggtgtgagactatagttagttgcgacggg tacgtcgttaaaagaatagctatcagtccaggcctgtatgggaagccttcaggctatgctgcta cgatgcaccgcgaggga ttcttgtgctgcaaagtgacagacacattgaacggggagagggtctc ttttcccgtgtgcacgtatgtgccagctacattgtgtgaccaaatgactggcatactggcaaca gatgtcagtgcggacgacgcgcaaaaactgctggttgggctcaaccagcgtatagtcgtcaacg gtcgcacccagagaaacaccaataccatgaaaaattaccttttgcccgtagtggcccaggcatt tgctaggtgggcaaaggaatataaggaagatcaagaagatgaaaggccactaggactacgagat agacagttagtcatggggtgttgttgggcttttagaaggcacaagataacatctatttataagc gcccggatacccaaaccatcatcaaagtgaacagcgatttccactcattcgtgctgcccaggat aggcagtaacacattggagatcgggctgagaacaagaatcaggaaaatgttagaggagcacaag gagccgtcacctctcattaccgccgaggacgtacaagaagctaagtgcgcagccgatgaggcta aggaggtgcgtgaagccgaggagttgcgcgcagctctaccacctttggcagctgatgttgagga gcccactctggaagccgatgtagacttgatgttacaagaggctggggccggctcagtggagaca cctcgtggcttgataaaggttaccagctacgatggcgaggacaagatcggctcttacgctgtgc tttctccgcaggctgtactcaagagtgaaaaattatcttgcatccaccctctcgctgaacaagt catagtgataacacactctggccgaaaagggcgttatgccgtggaaccataccatggtaaagta gtggtgccagagggacatgcaatacccgtccaggactttcaagctctgagtgaaagtgccacca ttgtgtacaacgaacgtgagttcgtaaacaggtacctgcacc atattgccacacatggaggagc gctgaacactgatgaagaatattacaaaactgtcaagcccagcgagcacgacggcgaatacctg tacgacatcgacaggaaacagtgcgtcaagaaagaactagtcactgggctagggctcacaggcg agctggtggatcctcccttccatgaattcgcctacgagagtctgagaacacgaccagccgctcc ttaccaagtaccaaccataggggtgtatggcgtgccaggatcaggcaagtctggcatcattaaa agcgcagtcaccaaaaaagatctagtggtgagcgccaagaaagaaaactgtgcagaaattataa gggacgtcaagaaaatgaaagggctggacgtcaatgccagaactgtggactcagtgctcttgaa tggatgcaaacaccccgtagagaccctgtatattgacgaagcttttgcttgtcatgcaggtact ctcagagcgctcatagccattataagacctaaaaaggcagtgctctgcggggatcccaaacagt gcggtttttttaacatgatgtgcctgaaagtgcattttaaccacgagatttgcacacaagtctt ccacaaaagcatctctcgccgttgcactaaatctgtgacttcggtcgtctcaaccttgttttac gacaaaaaaatgagaacgacgaatccgaaagagactaagattgtgattgacactaccggcagta ccaaacctaagcaggacgatctcattctcacttgtttcagagggtgggtgaagcagttgcaaat agattacaaaggcaacgaaataatgacggcagctgcctctcaagggctgacccgtaaaggtgtg tatgccgttcggtacaaggtgaatgaaaatcctctgtacgcacccacctcagaacatgtgaacg aa tcctactgacccgcacggaggaccgcatcgtgtggaaaacactagccggcgacccatggataaa cactgactgccaagtaccctgggaatttcactgccacgatagaggagtggcaagcagagcat gatgccatcatgaggcacatcttggagagaccggaccctaccgacgtcttccagaataaggcaa acgtgtgttgggccaaggctttagtgccggtgctgaagaccgctggcatagacatgaccactga acaatggaacactgtggattattttgaaacggacaaagctcactcagcagagatagtattgaac caactatgcgtgaggttctttggactcgatctggactccggtctattttctgcacccactgttc cgttatccattaggaataatcactgggataactccccgtcgcctaacatgtacgggctgaataa agaagtggtccgtcagctctctcgcaggtacccacaactgcctcgggcagttgccactggaaga gtctatgacatgaacactggtacactgcgcaattatgatccgcgcataaacctagtacctgtaa acagaagactgcctcatgctttagtcctccaccataatgaacacccacagagtgacttttcttc attcgtcagcaaattgaagggcagaactgtcctggtggtcggggaaaagttgtccgtcccaggc aaaatggttgactggttgtcagaccggcctgaggctaccttcagagctcggctggatttaggca tcccaggtgatgtgcccaaatatgacataatatttgttaatgtgaggaccccatataaatacca tcactatcagcagtgtgaagaccatgccattaagcttagcatgttgaccaagaaagcttgtctg catctgaatcccggcggaacctgtgtcagcataggttatggttacgctgacagggccagcgaaa gcatcattggtgctatagcgcggcagttcaagttttcccgggtatgcaaaccgaaatcctcact tgaagagacggaagttctgtttgtatt cattgggtacgatcgcaaggcccgtacgcacaatcct tacaagctttcatcaaccttgaccaacatttatacaggttccagactccacgaagccggatgtg caccctcatatcatgtggtgcgaggggatattgccacggccaccgaaggagtgattataaatgc tgctaacagcaaaggacaacctggcggaggggtgtgcggagcgctgtataagaaattcccggaa agcttcgatttacagccgatcgaagtaggaaaagcgcgactggtcaaaggtgcagctaaacata tcattcatgccgtaggaccaaacttcaacaaagtttcggaggttgaaggtgacaaacagttggc agaggcttatgagtccatcgctaagattgtcaacgataacaattacaagtcagtagcgattcca ctgttgtccaccggcatcttttccgggaacaaagatcgactaacccaatcattgaaccatttgc tgacagctttagacaccactgatgcagatgtagccatatactgcagggacaagaaatgggaaat gactctcaaggaagcagtggctaggagagaagcagtggaggagatatgcatatccgacgactct tcagtgacagaacctgatgcagagctggtgagggtgcatccgaagagttctttggctggaagga agggctacagcacaagcgatggcaaaactttctcatatttggaagggaccaagtttcaccaggc ggccaaggatatagcagaaattaatgccatgtggcccgttgcaacggaggccaatgagcaggta tgcatgtatatcctcggagaaagcatgagcagtattaggtcgaaatgccccgtcgaagagtcgg aagcctccacaccacctagcacgctgccttgcttgtgcatccatgccatgactccagaaagagt acagcgcctaaaagcctcacgtccagaacaaattactgtgtgctcatccttt ccattgccgaag tatagaatcactggtgtgcagaagatccaatgctcccagcctatattgttctcaccgaaagtgc ctgcgtatattcatccaaggaagtatctcgtggaaacaccaccggtagacgagactccggagcc atcggcagagaaccaatccacagaggggacacctgaacaaccaccacttataaccgaggatgag accaggactagaacgcctgagccgatcatcatcgaagaggaagaagaggatagcataagtttgc tgtcagatggcccgacccaccaggtgctgcaagtcgaggcagacattcacgggccgccctctgt atctagctcatcctggtccattcctcatgcatccgactttgatgtggacagtttatccatactt gacaccctggagggagctagcgtgaccagcggggcaacgtcagccgagactaactcttacttcg caaagagtatggagtttctggcgcgaccggtgcctgcgcctcgaacagtattcaggaaccctcc acatcccgctccgcgcacaagaacaccgtcacttgcacccagcagggcctgctcgagaaccagc ctagtttccaccccgccaggcgtgaatagggtgatcactagagaggagctcgaggcgcttaccc cgtcacgcactcctagcaggtcggtctcgagaaccagcctggtctccaacccgccaggcgtaaa tagggtgattacaagagaggagtttgaggcgttcgtagcacaacaacaatgacggtttgatgcg ggtgcatacatcttttcctccgacaccggtcaagggcatttacaacaaaaatcagtaaggcaaa cggtgctatccgaagtggtgttggagaggaccgaattggagatttcgtatgccccgcgcctcga ccaagaaaaagaagaattactacgcaagaaattacagttaaatcccacacctgctaacagaagc agataccagtcc aggaaggtggagaacatgaaagccataacagctagacgtattctgcaaggcc tagggcattatttgaaggcagaaggaaaagtggagtgctaccgaaccctgcatcctgttccttt gtattcatctagtgtgaaccgtgccttttcaagccccaaggtcgcagtggaagcctgtaacgcc atgttgaaagagaactttccgactgtggcttcttactgtattattccagagtacgatgcctatt tggacatggttgacggagcttcatgctgcttagacactgccagtttttgccctgcaaagctgcg cagctttccaaagaaacactcctatttggaacccacaatacgatcggcagtgccttcagcgatc cagaacacgctccagaacgtcctggcagctgccacaaaaagaaattgcaatgtcacgcaaatga gagaattgcccgtattggattcggcggcctttaatgtggaatgcttcaagaaatatgcgtgtaa taatgaatattgggaaacgtttaaagaaaaccccatcaggcttactgaagaaaacgtggtaaat tacattaccaaattaaaaggaccaaaagctgctgctctttttgcgaagacacataatttgaata tgttgcaggacataccaatggacaggtttgtaatggacttaaagagagacgtgaaagtgactcc aggaacaaaacatactgaagaacggcccaaggtacaggtgatccaggctgccgatccgctagca acagcgtatctgtgcggaatccaccgagagctggttaggagattaaatgcggtcctgcttccga acattcatacactgtttgatatgtcggctgaagactttgacgctattatagccgagcacttcca gcctggggattgtgttctggaaactgacatcgcgtcgtttgataaaagtgaggacgacgccatg gctctgaccgcgttaatgattctggaagacttaggtg tggacgcagagctgttgacgctgattg aggcggctttcggcgaaatttcatcaatacatttgcccactaaaactaaatttaaattcggagc catgatgaaatctggaatgttcctcacactgtttgtgaacacagtcattaacattgtaatcgca agcagagtgttgagagaacggctaaccggatcaccatgtgcagcattcattggagatgacaata tcgtgaaaggagtcaaatcggacaaattaatggcagacaggtgcgccacctggttgaatatgga agtcaagattatagatgctgtggtgggcgagaaagcgccttatttctgtggagggtttattttg tgtgactccgtgaccggcacagcgtgccgtgtggcagaccccctaaaaaggctgtttaagcttg gcaaacctctggcagcagacgatgaacatgatgatgacaggagaagggcattgcatgaagagtc aacacgctggaaccgagtgggtattctttcagagctgtgcaaggcagtagaatcaaggtatgaa accgtaggaacttccatcatagttatggccatgactactctagctagcagtgttaaatcattca gctacctgagaggggcccctataactctctacggctaacctgaatggactacgacatagtctag tcgagtctagtcgacgccaccatgttcgccctggtgctggccgtggtcatcctgcctctgtgga ccaccgccaacaagagctacgtgacccccacacccgccaccagatccatcggacacatgagcgc cctgctgagagagtacagcgaccggaacatgagcctgaagctggaagccttctaccccaccggc ttcgacgaggaactgatcaagagcctgcactggggcaacgaccggaagcacgtgttcctcgtga tcgtgaaagtgaaccccaccacccacgagggcgacgtcggcctggtcatcttccccaagtac ct gctgagcccctaccacttcaaggccgagcacagagcccccttccctgctggccgctttggcttt ctgagccaccctgtgacccccgacgtgtcattcttcgacagcagcttcgccccctacctgacca cacagcacctggtggccttcaccaccttcccccccaatcctctcgtgtggcacctggaaagagc cgagacagccgccaccgccgaaagaccttttggcgtgtccctgctgcccgccagacctaccgtg cccaagaacaccatcctggaacacaaggcccacttcgccacctgggatgccctggccagacaca ccttctttagcgccgaggccatcatcaccaacagcaccctgagaatccacgtgcccctgttcgg cagcgtgtggcccatcagatactgggccacaggcagcgtgctgctgaccagcgatagcggcaga gtggaagtgaacatcggcgtgggcttcatgagcagcctgatcagcctgagcagcggcctgccca tcgagctgattgtggtgccccacaccgtgaagctgaacgccgtgaccagcgacaccacctggtt ccagctgaacccccctggccctgatcctggccctagttacagagtgtacctgctgggcagaggc ctggacatgaacttcagcaagcacgccaccgtggacatctgcgcctaccctgaggaaagcctgg actacagataccacctgagcatggcccacaccgaggccctgagaatgaccaccaaggccgacca gcacgacatcaacgaggaaagctactaccacattgccgccagaatcgccaccagcatcttcgcc ctgagcgagatgggccggaccaccgagtactttctgctggacgagatcgtggacgtgcagtacc agctgaagttcctgaactacatcctgatgcggatcggcgctggcgcccaccctaataccatcag cggcaccagcgacctgatcttc gccgatcctagccagctgcacgacgagctgagcctgctgttc ggccaggtcaaacccgccaacgtggactacttcatcagctacgacgaggcccgggaccagctga aaacagcctacgccctgtccagaggccaggatcatgtgaacgccctgtccctggccaggcgcgt gatcatgagcatctacaagggcctgctggtcaagcagaacctgaacgccaccgagcggcaggcc ctgttcttcgccagcatgatcctgctgaacttcagagagggcctggaaaacagcagccgggtgc tggatggcagaaccaccctgctgctgatgaccagcatgtgcacagccgcccatgccacacaggc cgccctgaatatccaggaaggcctggcttacctgaaccccagcaagcacatgttcaccatcccc aacgtgtacagcccctgcatgggcagcctgagaaccgacctgaccgaagagatccacgtgatga acctgctgtccgccatccccaccagacccggactgaatgaggtgctgcacacccagctggacga gtccgagatcttcgacgccgccttcaagaccatgatgatctttaccacctggaccgccaaggac ctgcacatcctgcacacacacgtgcccgaggtgttcacatgccaagatgccgccgctcggaacg gcgagtatgtgctgattctgcctgccgtgcagggccacagctacgtgatcacccggaacaagcc ccagcggggcctggtgtatagcctggctgacgtggacgtgtacaaccccatcagcgtggtgtac ctgagcaaggatacctgcgtgtccgagcacggcgtgatcgaaacagtggccctgccccaccccg acaacctgaaagagtgcctgtactgcggctccgtgttcctgcggtatctgaccaccggcgccat catggacatcatcatcatcgacagcaaggacaccgagagacagctgg ccgccatgggcaacagc accatcccccccttcaaccccgacatgcacggcgacgatagcaaggccgtgctgctgttcccca acggcaccgtggtcacactgctgggcttcgagcggagacaggccatcagaatgagcggccagta cctgggcgcctctctgggtggtgcctttctggccgtcgtgggctttggcatcatcggctggatg ctgtgcggcaacagcagactgcgcgagtacaacaagatccccctgacctaatctagacgcggcc gcatacagcagcaattggcaagctgcttacatagaactcgcggcgattggcatgccgccttaaa atttttattttatttttcttttcttttccgaatcggattttgtttttaatatttcaaaaaaaaa aaaaaaaaaaaaaaaaaaaaaaaaaagggtcggcatggcatctccacctcctcgcggtccgacc tgggcatccgaaggaggacgcacgtccactcggatggctaagggagagccacgtttaaaccagc tccaattcgccctatagtgagtcgtattacgcgcgctcactggccgtcgttttacaacgtcgtg actgggaaaaccctggcgttacccaacttaatcgccttgcagcacatccccctttcgccagctg gcgtaatagcgaagaggcccgcaccgatcgcccttcccaacagttgcgcagcctgaatggcgaa tgggacgcgccctgtagcggcgcattaagcgcggcgggtgtggtggttacgcgcagcgtgaccg ctacacttgccagcgccctagcgcccgctcctttcgctttcttcccttcctttctcgccacgtt cgccggctttccccgtcaagctctaaatcgggggctccctttagggttccgatttagtgcttta cggcacctcgaccccaaaaaacttgattagggtgatggttcacgtagtgggccatcgccctgat agacggt ttttcgccctttgacgttggagtccacgttctttaatagtggactcttgttccaaac tggaacaacactcaaccctatctcggtctattcttttgatttataagggattttgccgatttcg gcctattggttaaaaaatgagctgatttaacaaaaatttaacgcgaattttaacaaaatattaa cgcttacaatttaggtggcacttttcggggaaatgtgcgcggaacccctatttgtttatttttc taaatacattcaaatatgtatccgctcatgagacaataaccctgataaatgcttcaataatatt gaaaaaggaagagtatgagtattcaacatttccgtgtcgcccttattcccttttttgcggcatt ttgccttcctgtttttgctcacccagaaacgctggtgaaagtaaaagatgctgaagatcagttg ggtgcacgagtgggttacatcgaactggatctcaacagcggtaagatccttgagagttttcgcc ccgaagaacgttttccaatgatgagcacttttaaagttctgctatgtggcgcggtattatcccg tattgacgccgggcaagagcaactcggtcgccgcatacactattctcagaatgacttggttgag tactcaccagtcacagaaaagcatcttacggatggcatgacagtaagagaattatgcagtgctg ccataaccatgagtgataacactgcggccaacttacttctgacaacgatcggaggaccgaagga gctaaccgcttttttgcacaacatgggggatcatgtaactcgccttgatcgttgggaaccggag ctgaatgaagccataccaaacgacgagcgtgacaccacgatgcctgtagcaatggcaacaacgt tgcgcaaactattaactggcgaactacttactctagcttcccggcaacaattaatagactggat ggaggcggataaagttgcaggaccacttctgc gctcggcccttccggctggctggtttattgct gataaatctggagccggtgagcgtgggtctcgcggtatcattgcagcactggggccagatggta agccctcccgtatcgtagttatctacacgacggggagtcaggcaactatggatgaacgaaatag acagatcgctgagataggtgcctcactgattaagcattggtaactgtcagaccaagtttactca tatatactttagattgatttaaaacttcatttttaatttaaaaggatctaggtgaagatccttt ttgataatctcatgaccaaaatcccttaacgtgagttttcgttccactgagcgtcagaccccgt agaaaagatcaaaggatcttcttgagatcctttttttctgcgcgtaatctgctgcttgcaaaca aaaaaaccaccgctaccagcggtggtttgtttgccggatcaagagctaccaactctttttccga aggtaactggcttcagcagagcgcagataccaaatactgttcttctagtgtagccgtagttagg ccaccacttcaagaactctgtagcaccgcctacatacctcgctctgctaatcctgttaccagtg gctgctgccagtggcgataagtcgtgtcttaccgggttggactcaagacgatagttaccggata aggcgcagcggtcgggctgaacggggggttcgtgcacacagcccagcttggagcgaacgaccta caccgaactgagatacctacagcgtgagctatgagaaagcgccacgcttcccgaagggagaaag gcggacaggtatccggtaagcggcagggtcggaacaggagagcgcacgagggagcttccagggg gaaacgcctggtatctttatagtcctgtcgggtttcgccacctctgacttgagcgtcgattttt gtgatgctcgtcaggggggcggagcctatggaaaaacgccagcaacgcggccttttt acggttc ctggccttttgctggccttttgctcacatgttctttcctgcgttatcccctgattctgtggata accgtattaccgcctttgagtgagctgataccgctcgccgcagccgaacgaccgagcgcagcga gtcagtgagcgaggaagcggaagagcgcccaatacgcaaaccgcctctccccgcgcgttggccg attcattaatgcagctggcacgacaggtttcccgactggaaagcgggcagtgagcgcaacgcaa ttaatgtgagttagctcactcattaggcaccccaggctttacactttatgctcccggctcgtat gttgtgtggaattgtgagcggataacaatttcacacaggaaacagctatgaccatgattacgcc aagcgcgcaattaaccctcactaaagggaacaaaagctgggtaccgggcccacgcgtaatacga ctcactatag_13258 VZV VEERep. SGPgL 1_ataggcggcgcatgagagaagcccagaccaattacctacccaaaatggagaaagttcacgttga catcgaggaagacagcccattcctcagagctttgcagcggagcttcccgcagtttgaggtagaa gccaagcaggtcactgataatgaccatgctaatgccagagcgttttcgcatctggcttcaaaac tgatcgaaacggaggtggacccatccgacacgatccttgacattggaagtgcgcccgcccgcag aatgtattctaagcacaagtatcattgtatctgtccgatgagatgtgcggaagatccggacaga ttgtataagtatgcaactaagctgaagaaaaactgtaaggaaataactgataaggaattggaca agaaaatgaaggagctcgccgccgtcatgagcgaccctgacctggaaactgagactatgtgcct ccacgacgacgagtcgtgtcgctacgaagggcaagtcgctgtttaccaggatgtatacgcggtt gacggaccgacaagtctctatcaccaagccaataagggagttagagtcgcctactggataggct ttgacaccaccccttttatgtttaagaacttggctggagcatatccatcatactctaccaactg ggccgacgaaaccgtgttaacggctcgtaacataggcctatgcagctctgacgttatggagcgg tcacgtagagggatgtccattcttagaaagaagtatttgaaaccatccaacaatgttctattct ctgttggctcgaccatctaccacgagaagagggacttactgaggagctggcacctgccgtctgt atttcacttacgtggcaagcaaaattacacatgtcggtgtgagactatagttagttgcgacggg tacgtcgttaaaagaatagctatcagtccaggcctgtatgggaagccttcaggctatgctgcta cgatgcaccgcgaggga ttcttgtgctgcaaagtgacagacacattgaacggggagagggtctc ttttcccgtgtgcacgtatgtgccagctacattgtgtgaccaaatgactggcatactggcaaca gatgtcagtgcggacgacgcgcaaaaactgctggttgggctcaaccagcgtatagtcgtcaacg gtcgcacccagagaaacaccaataccatgaaaaattaccttttgcccgtagtggcccaggcatt tgctaggtgggcaaaggaatataaggaagatcaagaagatgaaaggccactaggactacgagat agacagttagtcatggggtgttgttgggcttttagaaggcacaagataacatctatttataagc gcccggatacccaaaccatcatcaaagtgaacagcgatttccactcattcgtgctgcccaggat aggcagtaacacattggagatcgggctgagaacaagaatcaggaaaatgttagaggagcacaag gagccgtcacctctcattaccgccgaggacgtacaagaagctaagtgcgcagccgatgaggcta aggaggtgcgtgaagccgaggagttgcgcgcagctctaccacctttggcagctgatgttgagga gcccactctggaagccgatgtagacttgatgttacaagaggctggggccggctcagtggagaca cctcgtggcttgataaaggttaccagctacgatggcgaggacaagatcggctcttacgctgtgc tttctccgcaggctgtactcaagagtgaaaaattatcttgcatccaccctctcgctgaacaagt catagtgataacacactctggccgaaaagggcgttatgccgtggaaccataccatggtaaagta gtggtgccagagggacatgcaatacccgtccaggactttcaagctctgagtgaaagtgccacca ttgtgtacaacgaacgtgagttcgtaaacaggtacctgcacc atattgccacacatggaggagc gctgaacactgatgaagaatattacaaaactgtcaagcccagcgagcacgacggcgaatacctg tacgacatcgacaggaaacagtgcgtcaagaaagaactagtcactgggctagggctcacaggcg agctggtggatcctcccttccatgaattcgcctacgagagtctgagaacacgaccagccgctcc ttaccaagtaccaaccataggggtgtatggcgtgccaggatcaggcaagtctggcatcattaaa agcgcagtcaccaaaaaagatctagtggtgagcgccaagaaagaaaactgtgcagaaattataa gggacgtcaagaaaatgaaagggctggacgtcaatgccagaactgtggactcagtgctcttgaa tggatgcaaacaccccgtagagaccctgtatattgacgaagcttttgcttgtcatgcaggtact ctcagagcgctcatagccattataagacctaaaaaggcagtgctctgcggggatcccaaacagt gcggtttttttaacatgatgtgcctgaaagtgcattttaaccacgagatttgcacacaagtctt ccacaaaagcatctctcgccgttgcactaaatctgtgacttcggtcgtctcaaccttgttttac gacaaaaaaatgagaacgacgaatccgaaagagactaagattgtgattgacactaccggcagta ccaaacctaagcaggacgatctcattctcacttgtttcagagggtgggtgaagcagttgcaaat agattacaaaggcaacgaaataatgacggcagctgcctctcaagggctgacccgtaaaggtgtg tatgccgttcggtacaaggtgaatgaaaatcctctgtacgcacccacctcagaacatgtgaacg aa tcctactgacccgcacggaggaccgcatcgtgtggaaaacactagccggcgacccatggataaa cactgactgccaagtaccctgggaatttcactgccacgatagaggagtggcaagcagagcat gatgccatcatgaggcacatcttggagagaccggaccctaccgacgtcttccagaataaggcaa acgtgtgttgggccaaggctttagtgccggtgctgaagaccgctggcatagacatgaccactga acaatggaacactgtggattattttgaaacggacaaagctcactcagcagagatagtattgaac caactatgcgtgaggttctttggactcgatctggactccggtctattttctgcacccactgttc cgttatccattaggaataatcactgggataactccccgtcgcctaacatgtacgggctgaataa agaagtggtccgtcagctctctcgcaggtacccacaactgcctcgggcagttgccactggaaga gtctatgacatgaacactggtacactgcgcaattatgatccgcgcataaacctagtacctgtaa acagaagactgcctcatgctttagtcctccaccataatgaacacccacagagtgacttttcttc attcgtcagcaaattgaagggcagaactgtcctggtggtcggggaaaagttgtccgtcccaggc aaaatggttgactggttgtcagaccggcctgaggctaccttcagagctcggctggatttaggca tcccaggtgatgtgcccaaatatgacataatatttgttaatgtgaggaccccatataaatacca tcactatcagcagtgtgaagaccatgccattaagcttagcatgttgaccaagaaagcttgtctg catctgaatcccggcggaacctgtgtcagcataggttatggttacgctgacagggccagcgaaa gcatcattggtgctatagcgcggcagttcaagttttcccgggtatgcaaaccgaaatcctcact tgaagagacggaagttctgtttgtatt cattgggtacgatcgcaaggcccgtacgcacaatcct tacaagctttcatcaaccttgaccaacatttatacaggttccagactccacgaagccggatgtg caccctcatatcatgtggtgcgaggggatattgccacggccaccgaaggagtgattataaatgc tgctaacagcaaaggacaacctggcggaggggtgtgcggagcgctgtataagaaattcccggaa agcttcgatttacagccgatcgaagtaggaaaagcgcgactggtcaaaggtgcagctaaacata tcattcatgccgtaggaccaaacttcaacaaagtttcggaggttgaaggtgacaaacagttggc agaggcttatgagtccatcgctaagattgtcaacgataacaattacaagtcagtagcgattcca ctgttgtccaccggcatcttttccgggaacaaagatcgactaacccaatcattgaaccatttgc tgacagctttagacaccactgatgcagatgtagccatatactgcagggacaagaaatgggaaat gactctcaaggaagcagtggctaggagagaagcagtggaggagatatgcatatccgacgactct tcagtgacagaacctgatgcagagctggtgagggtgcatccgaagagttctttggctggaagga agggctacagcacaagcgatggcaaaactttctcatatttggaagggaccaagtttcaccaggc ggccaaggatatagcagaaattaatgccatgtggcccgttgcaacggaggccaatgagcaggta tgcatgtatatcctcggagaaagcatgagcagtattaggtcgaaatgccccgtcgaagagtcgg aagcctccacaccacctagcacgctgccttgcttgtgcatccatgccatgactccagaaagagt acagcgcctaaaagcctcacgtccagaacaaattactgtgtgctcatccttt ccattgccgaag tatagaatcactggtgtgcagaagatccaatgctcccagcctatattgttctcaccgaaagtgc ctgcgtatattcatccaaggaagtatctcgtggaaacaccaccggtagacgagactccggagcc atcggcagagaaccaatccacagaggggacacctgaacaaccaccacttataaccgaggatgag accaggactagaacgcctgagccgatcatcatcgaagaggaagaagaggatagcataagtttgc tgtcagatggcccgacccaccaggtgctgcaagtcgaggcagacattcacgggccgccctctgt atctagctcatcctggtccattcctcatgcatccgactttgatgtggacagtttatccatactt gacaccctggagggagctagcgtgaccagcggggcaacgtcagccgagactaactcttacttcg caaagagtatggagtttctggcgcgaccggtgcctgcgcctcgaacagtattcaggaaccctcc acatcccgctccgcgcacaagaacaccgtcacttgcacccagcagggcctgctcgagaaccagc ctagtttccaccccgccaggcgtgaatagggtgatcactagagaggagctcgaggcgcttaccc cgtcacgcactcctagcaggtcggtctcgagaaccagcctggtctccaacccgccaggcgtaaa tagggtgattacaagagaggagtttgaggcgttcgtagcacaacaacaatgacggtttgatgcg ggtgcatacatcttttcctccgacaccggtcaagggcatttacaacaaaaatcagtaaggcaaa cggtgctatccgaagtggtgttggagaggaccgaattggagatttcgtatgccccgcgcctcga ccaagaaaaagaagaattactacgcaagaaattacagttaaatcccacacctgctaacagaagc agataccagtcc aggaaggtggagaacatgaaagccataacagctagacgtattctgcaaggcc tagggcattatttgaaggcagaaggaaaagtggagtgctaccgaaccctgcatcctgttccttt gtattcatctagtgtgaaccgtgccttttcaagccccaaggtcgcagtggaagcctgtaacgcc atgttgaaagagaactttccgactgtggcttcttactgtattattccagagtacgatgcctatt tggacatggttgacggagcttcatgctgcttagacactgccagtttttgccctgcaaagctgcg cagctttccaaagaaacactcctatttggaacccacaatacgatcggcagtgccttcagcgatc cagaacacgctccagaacgtcctggcagctgccacaaaaagaaattgcaatgtcacgcaaatga gagaattgcccgtattggattcggcggcctttaatgtggaatgcttcaagaaatatgcgtgtaa taatgaatattgggaaacgtttaaagaaaaccccatcaggcttactgaagaaaacgtggtaaat tacattaccaaattaaaaggaccaaaagctgctgctctttttgcgaagacacataatttgaata tgttgcaggacataccaatggacaggtttgtaatggacttaaagagagacgtgaaagtgactcc aggaacaaaacatactgaagaacggcccaaggtacaggtgatccaggctgccgatccgctagca acagcgtatctgtgcggaatccaccgagagctggttaggagattaaatgcggtcctgcttccga acattcatacactgtttgatatgtcggctgaagactttgacgctattatagccgagcacttcca gcctggggattgtgttctggaaactgacatcgcgtcgtttgataaaagtgaggacgacgccatg gctctgaccgcgttaatgattctggaagacttaggtg tggacgcagagctgttgacgctgattg aggcggctttcggcgaaatttcatcaatacatttgcccactaaaactaaatttaaattcggagc catgatgaaatctggaatgttcctcacactgtttgtgaacacagtcattaacattgtaatcgca agcagagtgttgagagaacggctaaccggatcaccatgtgcagcattcattggagatgacaata tcgtgaaaggagtcaaatcggacaaattaatggcagacaggtgcgccacctggttgaatatgga agtcaagattatagatgctgtggtgggcgagaaagcgccttatttctgtggagggtttattttg tgtgactccgtgaccggcacagcgtgccgtgtggcagaccccctaaaaaggctgtttaagcttg gcaaacctctggcagcagacgatgaacatgatgatgacaggagaagggcattgcatgaagagtc aacacgctggaaccgagtgggtattctttcagagctgtgcaaggcagtagaatcaaggtatgaa accgtaggaacttccatcatagttatggccatgactactctagctagcagtgttaaatcattca gctacctgagaggggcccctataactctctacggctaacctgaatggactacgacatagtctag tcgagtctagtcgacgccaccatggccagccacaagtggctgctgcagatgatcgtgttcctga aaaccatcacaatcgcctactgcctgcatctgcaggacgacacccctctgttcttcggcgccaa gcctctgagcgacgtgtccctgatcatcaccgagccttgcgtgtccagcgtgtacgaggcctgg gattatgccgcccctcccgtgtccaatctgagcgaagccctgagcggcatcgtggtcaagacca agtgccccgtgcccgaagtgatcctgtggttcaaggacaagcagatggcctactggaccaac cc ttacgtgaccctgaagggcctgacccagagcgtgggcgaggaacacaagagcggcgacatcaga gatgccctgctggatgccctgtccggtgtctgggtggacagcacaccctccagcaccaacatcc ccgagaacggctgtgtgtggggagccgaccggctgttccagagagtgtgtcagtaatctagacg cggccgcatacagcagcaattggcaagctgcttacatagaactcgcggcgattggcatgccgcc ttaaaatttttattttatttttcttttcttttccgaatcggattttgtttttaatatttcaaaa aaaaaaaaaaaaaaaaaaaaaaaaaaaaaaagggtcggcatggcatctccacctcctcgcggtc cgacctgggcatccgaaggaggacgcacgtccactcggatggctaagggagagccacgtttaaa ccagctccaattcgccctatagtgagtcgtattacgcgcgctcactggccgtcgttttacaacg tcgtgactgggaaaaccctggcgttacccaacttaatcgccttgcagcacatccccctttcgcc agctggcgtaatagcgaagaggcccgcaccgatcgcccttcccaacagttgcgcagcctgaatg gcgaatgggacgcgccctgtagcggcgcattaagcgcggcgggtgtggtggttacgcgcagcgt gaccgctacacttgccagcgccctagcgcccgctcctttcgctttcttcccttcctttctcgcc acgttcgccggctttccccgtcaagctctaaatcgggggctccctttagggttccgatttagtg ctttacggcacctcgaccccaaaaaacttgattagggtgatggttcacgtagtgggccatcgcc ctgatagacggtttttcgccctttgacgttggagtccacgttctttaatagtggactcttgttc caaactggaacaacactcaacc ctatctcggtctattcttttgatttataagggattttgccga tttcggcctattggttaaaaaatgagctgatttaacaaaaatttaacgcgaattttaacaaaat attaacgcttacaatttaggtggcacttttcggggaaatgtgcgcggaacccctatttgtttat ttttctaaatacattcaaatatgtatccgctcatgagacaataaccctgataaatgcttcaata atattgaaaaaggaagagtatgagtattcaacatttccgtgtcgcccttattcccttttttgcg gcattttgccttcctgtttttgctcacccagaaacgctggtgaaagtaaaagatgctgaagatc agttgggtgcacgagtgggttacatcgaactggatctcaacagcggtaagatccttgagagttt tcgccccgaagaacgttttccaatgatgagcacttttaaagttctgctatgtggcgcggtatta tcccgtattgacgccgggcaagagcaactcggtcgccgcatacactattctcagaatgacttgg ttgagtactcaccagtcacagaaaagcatcttacggatggcatgacagtaagagaattatgcag tgctgccataaccatgagtgataacactgcggccaacttacttctgacaacgatcggaggaccg aaggagctaaccgcttttttgcacaacatgggggatcatgtaactcgccttgatcgttgggaac cggagctgaatgaagccataccaaacgacgagcgtgacaccacgatgcctgtagcaatggcaac aacgttgcgcaaactattaactggcgaactacttactctagcttcccggcaacaattaatagac tggatggaggcggataaagttgcaggaccacttctgcgctcggcccttccggctggctggttta ttgctgataaatctggagccggtgagcgtgggtctcgcggtatcatt gcagcactggggccaga tggtaagccctcccgtatcgtagttatctacacgacggggagtcaggcaactatggatgaacga aatagacagatcgctgagataggtgcctcactgattaagcattggtaactgtcagaccaagttt actcatatatactttagattgatttaaaacttcatttttaatttaaaaggatctaggtgaagat cctttttgataatctcatgaccaaaatcccttaacgtgagttttcgttccactgagcgtcagac cccgtagaaaagatcaaaggatcttcttgagatcctttttttctgcgcgtaatctgctgcttgc aaacaaaaaaaccaccgctaccagcggtggtttgtttgccggatcaagagctaccaactctttt tccgaaggtaactggcttcagcagagcgcagataccaaatactgttcttctagtgtagccgtag ttaggccaccacttcaagaactctgtagcaccgcctacatacctcgctctgctaatcctgttac cagtggctgctgccagtggcgataagtcgtgtcttaccgggttggactcaagacgatagttacc ggataaggcgcagcggtcgggctgaacggggggttcgtgcacacagcccagcttggagcgaacg acctacaccgaactgagatacctacagcgtgagctatgagaaagcgccacgcttcccgaaggga gaaaggcggacaggtatccggtaagcggcagggtcggaacaggagagcgcacgagggagcttcc agggggaaacgcctggtatctttatagtcctgtcgggtttcgccacctctgacttgagcgtcga tttttgtgatgctcgtcaggggggcggagcctatggaaaaacgccagcaacgcggcctttttac ggttcctggccttttgctggccttttgctcacatgttctttcctgcgttatcccctgattctgt ggataac cgtattaccgcctttgagtgagctgataccgctcgccgcagccgaacgaccgagcgc agcgagtcagtgagcgaggaagcggaagagcgcccaatacgcaaaccgcctctccccgcgcgtt ggccgattcattaatgcagctggcacgacaggtttcccgactggaaagcgggcagtgagcgcaa cgcaattaatgtgagttagctcactcattaggcaccccaggctttacactttatgctcccggct cgtatgttgtgtggaattgtgagcggataacaatttcacacaggaaacagctatgaccatgatt acgccaagcgcgcaattaaccctcactaaagggaacaaaagctgggtaccgggcccacgcgtaa tacgactcactatag_11215 VZV VEERep. SGPgH-SGPgL 1_ataggcggcgcatgagagaagcccagaccaattacctacccaaaatggagaaagttcacgttga catcgaggaagacagcccattcctcagagctttgcagcggagcttcccgcagtttgaggtagaa gccaagcaggtcactgataatgaccatgctaatgccagagcgttttcgcatctggcttcaaaac tgatcgaaacggaggtggacccatccgacacgatccttgacattggaagtgcgcccgcccgcag aatgtattctaagcacaagtatcattgtatctgtccgatgagatgtgcggaagatccggacaga ttgtataagtatgcaactaagctgaagaaaaactgtaaggaaataactgataaggaattggaca agaaaatgaaggagctcgccgccgtcatgagcgaccctgacctggaaactgagactatgtgcct ccacgacgacgagtcgtgtcgctacgaagggcaagtcgctgtttaccaggatgtatacgcggtt gacggaccgacaagtctctatcaccaagccaataagggagttagagtcgcctactggataggct ttgacaccaccccttttatgtttaagaacttggctggagcatatccatcatactctaccaactg ggccgacgaaaccgtgttaacggctcgtaacataggcctatgcagctctgacgttatggagcgg tcacgtagagggatgtccattcttagaaagaagtatttgaaaccatccaacaatgttctattct ctgttggctcgaccatctaccacgagaagagggacttactgaggagctggcacctgccgtctgt atttcacttacgtggcaagcaaaattacacatgtcggtgtgagactatagttagttgcgacggg tacgtcgttaaaagaatagctatcagtccaggcctgtatgggaagccttcaggctatgctgcta cgatgcaccgc gagggattcttgtgctgcaaagtgacagacacattgaacggggagagggtctc ttttcccgtgtgcacgtatgtgccagctacattgtgtgaccaaatgactggcatactggcaaca gatgtcagtgcggacgacgcgcaaaaactgctggttgggctcaaccagcgtatagtcgtcaacg gtcgcacccagagaaacaccaataccatgaaaaattaccttttgcccgtagtggcccaggcatt tgctaggtgggcaaaggaatataaggaagatcaagaagatgaaaggccactaggactacgagat agacagttagtcatggggtgttgttgggcttttagaaggcacaagataacatctatttataagc gcccggatacccaaaccatcatcaaagtgaacagcgatttccactcattcgtgctgcccaggat aggcagtaacacattggagatcgggctgagaacaagaatcaggaaaatgttagaggagcacaag gagccgtcacctctcattaccgccgaggacgtacaagaagctaagtgcgcagccgatgaggcta aggaggtgcgtgaagccgaggagttgcgcgcagctctaccacctttggcagctgatgttgagga gcccactctggaagccgatgtagacttgatgttacaagaggctggggccggctcagtggagaca cctcgtggcttgataaaggttaccagctacgatggcgaggacaagatcggctcttacgctgtgc tttctccgcaggctgtactcaagagtgaaaaattatcttgcatccaccctctcgctgaacaagt catagtgataacacactctggccgaaaagggcgttatgccgtggaaccataccatggtaaagta gtggtgccagagggacatgcaatacccgtccaggactttcaagctctgagtgaaagtgccacca ttgtgtacaacgaacgtgagttcgtaaacaggtacc tgcaccatattgccacacatggaggagc gctgaacactgatgaagaatattacaaaactgtcaagcccagcgagcacgacggcgaatacctg tacgacatcgacaggaaacagtgcgtcaagaaagaactagtcactgggctagggctcacaggcg agctggtggatcctcccttccatgaattcgcctacgagagtctgagaacacgaccagccgctcc ttaccaagtaccaaccataggggtgtatggcgtgccaggatcaggcaagtctggcatcattaaa agcgcagtcaccaaaaaagatctagtggtgagcgccaagaaagaaaactgtgcagaaattataa gggacgtcaagaaaatgaaagggctggacgtcaatgccagaactgtggactcagtgctcttgaa tggatgcaaacaccccgtagagaccctgtatattgacgaagcttttgcttgtcatgcaggtact ctcagagcgctcatagccattataagacctaaaaaggcagtgctctgcggggatcccaaacagt gcggtttttttaacatgatgtgcctgaaagtgcattttaaccacgagatttgcacacaagtctt ccacaaaagcatctctcgccgttgcactaaatctgtgacttcggtcgtctcaaccttgttttac gacaaaaaaatgagaacgacgaatccgaaagagactaagattgtgattgacactaccggcagta ccaaacctaagcaggacgatctcattctcacttgtttcagagggtgggtgaagcagttgcaaat agattacaaaggcaacgaaataatgacggcagctgcctctcaagggctgacccgtaaaggtgtg tatgccgttcggtacaaggtgaatgaaaatcctctgtacgcacccacctcagaacatgtgaacg tcctactgacccgcacggaggaccgcatcgtgtggaaaacactagccggcgacccatggat aaa aacactgactgccaagtaccctgggaatttcactgccacgatagaggagtggcaagcagagcat gatgccatcatgaggcacatcttggagagaccggaccctaccgacgtcttccagaataaggcaa acgtgtgttgggccaaggctttagtgccggtgctgaagaccgctggcatagacatgaccactga acaatggaacactgtggattattttgaaacggacaaagctcactcagcagagatagtattgaac caactatgcgtgaggttctttggactcgatctggactccggtctattttctgcacccactgttc cgttatccattaggaataatcactgggataactccccgtcgcctaacatgtacgggctgaataa agaagtggtccgtcagctctctcgcaggtacccacaactgcctcgggcagttgccactggaaga gtctatgacatgaacactggtacactgcgcaattatgatccgcgcataaacctagtacctgtaa acagaagactgcctcatgctttagtcctccaccataatgaacacccacagagtgacttttcttc attcgtcagcaaattgaagggcagaactgtcctggtggtcggggaaaagttgtccgtcccaggc aaaatggttgactggttgtcagaccggcctgaggctaccttcagagctcggctggatttaggca tcccaggtgatgtgcccaaatatgacataatatttgttaatgtgaggaccccatataaatacca tcactatcagcagtgtgaagaccatgccattaagcttagcatgttgaccaagaaagcttgtctg catctgaatcccggcggaacctgtgtcagcataggttatggttacgctgacagggccagcgaaa gcatcattggtgctatagcgcggcagttcaagttttcccgggtatgcaaaccgaaatcctcact tgaagagacggaagttctgtt tgtattcattgggtacgatcgcaaggcccgtacgcacaatcct tacaagctttcatcaaccttgaccaacatttatacaggttccagactccacgaagccggatgtg caccctcatatcatgtggtgcgaggggatattgccacggccaccgaaggagtgattataaatgc tgctaacagcaaaggacaacctggcggaggggtgtgcggagcgctgtataagaaattcccggaa agcttcgatttacagccgatcgaagtaggaaaagcgcgactggtcaaaggtgcagctaaacata tcattcatgccgtaggaccaaacttcaacaaagtttcggaggttgaaggtgacaaacagttggc agaggcttatgagtccatcgctaagattgtcaacgataacaattacaagtcagtagcgattcca ctgttgtccaccggcatcttttccgggaacaaagatcgactaacccaatcattgaaccatttgc tgacagctttagacaccactgatgcagatgtagccatatactgcagggacaagaaatgggaaat gactctcaaggaagcagtggctaggagagaagcagtggaggagatatgcatatccgacgactct tcagtgacagaacctgatgcagagctggtgagggtgcatccgaagagttctttggctggaagga agggctacagcacaagcgatggcaaaactttctcatatttggaagggaccaagtttcaccaggc ggccaaggatatagcagaaattaatgccatgtggcccgttgcaacggaggccaatgagcaggta tgcatgtatatcctcggagaaagcatgagcagtattaggtcgaaatgccccgtcgaagagtcgg aagcctccacaccacctagcacgctgccttgcttgtgcatccatgccatgactccagaaagagt acagcgcctaaaagcctcacgtccagaacaaattactgtgtgctca tcctttccattgccgaag tatagaatcactggtgtgcagaagatccaatgctcccagcctatattgttctcaccgaaagtgc ctgcgtatattcatccaaggaagtatctcgtggaaacaccaccggtagacgagactccggagcc atcggcagagaaccaatccacagaggggacacctgaacaaccaccacttataaccgaggatgag accaggactagaacgcctgagccgatcatcatcgaagaggaagaagaggatagcataagtttgc tgtcagatggcccgacccaccaggtgctgcaagtcgaggcagacattcacgggccgccctctgt atctagctcatcctggtccattcctcatgcatccgactttgatgtggacagtttatccatactt gacaccctggagggagctagcgtgaccagcggggcaacgtcagccgagactaactcttacttcg caaagagtatggagtttctggcgcgaccggtgcctgcgcctcgaacagtattcaggaaccctcc acatcccgctccgcgcacaagaacaccgtcacttgcacccagcagggcctgctcgagaaccagc ctagtttccaccccgccaggcgtgaatagggtgatcactagagaggagctcgaggcgcttaccc cgtcacgcactcctagcaggtcggtctcgagaaccagcctggtctccaacccgccaggcgtaaa tagggtgattacaagagaggagtttgaggcgttcgtagcacaacaacaatgacggtttgatgcg ggtgcatacatcttttcctccgacaccggtcaagggcatttacaacaaaaatcagtaaggcaaa cggtgctatccgaagtggtgttggagaggaccgaattggagatttcgtatgccccgcgcctcga ccaagaaaaagaagaattactacgcaagaaattacagttaaatcccacacctgctaacagaagc agatac cagtccaggaaggtggagaacatgaaagccataacagctagacgtattctgcaaggcc tagggcattatttgaaggcagaaggaaaagtggagtgctaccgaaccctgcatcctgttccttt gtattcatctagtgtgaaccgtgccttttcaagccccaaggtcgcagtggaagcctgtaacgcc atgttgaaagagaactttccgactgtggcttcttactgtattattccagagtacgatgcctatt tggacatggttgacggagcttcatgctgcttagacactgccagtttttgccctgcaaagctgcg cagctttccaaagaaacactcctatttggaacccacaatacgatcggcagtgccttcagcgatc cagaacacgctccagaacgtcctggcagctgccacaaaaagaaattgcaatgtcacgcaaatga gagaattgcccgtattggattcggcggcctttaatgtggaatgcttcaagaaatatgcgtgtaa taatgaatattgggaaacgtttaaagaaaaccccatcaggcttactgaagaaaacgtggtaaat tacattaccaaattaaaaggaccaaaagctgctgctctttttgcgaagacacataatttgaata tgttgcaggacataccaatggacaggtttgtaatggacttaaagagagacgtgaaagtgactcc aggaacaaaacatactgaagaacggcccaaggtacaggtgatccaggctgccgatccgctagca acagcgtatctgtgcggaatccaccgagagctggttaggagattaaatgcggtcctgcttccga acattcatacactgtttgatatgtcggctgaagactttgacgctattatagccgagcacttcca gcctggggattgtgttctggaaactgacatcgcgtcgtttgataaaagtgaggacgacgccatg gctctgaccgcgttaatgattctggaagact taggtgtggacgcagagctgttgacgctgattg aggcggctttcggcgaaatttcatcaatacatttgcccactaaaactaaatttaaattcggagc catgatgaaatctggaatgttcctcacactgtttgtgaacacagtcattaacattgtaatcgca agcagagtgttgagagaacggctaaccggatcaccatgtgcagcattcattggagatgacaata tcgtgaaaggagtcaaatcggacaaattaatggcagacaggtgcgccacctggttgaatatgga agtcaagattatagatgctgtggtgggcgagaaagcgccttatttctgtggagggtttattttg tgtgactccgtgaccggcacagcgtgccgtgtggcagaccccctaaaaaggctgtttaagcttg gcaaacctctggcagcagacgatgaacatgatgatgacaggagaagggcattgcatgaagagtc aacacgctggaaccgagtgggtattctttcagagctgtgcaaggcagtagaatcaaggtatgaa accgtaggaacttccatcatagttatggccatgactactctagctagcagtgttaaatcattca gctacctgagaggggcccctataactctctacggctaacctgaatggactacgacatagtctag tcgagtctagtcgacgccaccatgttcgccctggtgctggccgtggtcatcctgcctctgtgga ccaccgccaacaagagctacgtgacccccacacccgccaccagatccatcggacacatgagcgc cctgctgagagagtacagcgaccggaacatgagcctgaagctggaagccttctaccccaccggc ttcgacgaggaactgatcaagagcctgcactggggcaacgaccggaagcacgtgttcctcgtga tcgtgaaagtgaaccccaccacccacgagggcgacgtcggcctggtcatcttcccc aagtacct gctgagcccctaccacttcaaggccgagcacagagcccccttccctgctggccgctttggcttt ctgagccaccctgtgacccccgacgtgtcattcttcgacagcagcttcgccccctacctgacca cacagcacctggtggccttcaccaccttcccccccaatcctctcgtgtggcacctggaaagagc cgagacagccgccaccgccgaaagaccttttggcgtgtccctgctgcccgccagacctaccgtg cccaagaacaccatcctggaacacaaggcccacttcgccacctgggatgccctggccagacaca ccttctttagcgccgaggccatcatcaccaacagcaccctgagaatccacgtgcccctgttcgg cagcgtgtggcccatcagatactgggccacaggcagcgtgctgctgaccagcgatagcggcaga gtggaagtgaacatcggcgtgggcttcatgagcagcctgatcagcctgagcagcggcctgccca tcgagctgattgtggtgccccacaccgtgaagctgaacgccgtgaccagcgacaccacctggtt ccagctgaacccccctggccctgatcctggccctagttacagagtgtacctgctgggcagaggc ctggacatgaacttcagcaagcacgccaccgtggacatctgcgcctaccctgaggaaagcctgg actacagataccacctgagcatggcccacaccgaggccctgagaatgaccaccaaggccgacca gcacgacatcaacgaggaaagctactaccacattgccgccagaatcgccaccagcatcttcgcc ctgagcgagatgggccggaccaccgagtactttctgctggacgagatcgtggacgtgcagtacc agctgaagttcctgaactacatcctgatgcggatcggcgctggcgcccaccctaataccatcag cggcaccagcgacctg atcttcgccgatcctagccagctgcacgacgagctgagcctgctgttc ggccaggtcaaacccgccaacgtggactacttcatcagctacgacgaggcccgggaccagctga aaacagcctacgccctgtccagaggccaggatcatgtgaacgccctgtccctggccaggcgcgt gatcatgagcatctacaagggcctgctggtcaagcagaacctgaacgccaccgagcggcaggcc ctgttcttcgccagcatgatcctgctgaacttcagagagggcctggaaaacagcagccgggtgc tggatggcagaaccaccctgctgctgatgaccagcatgtgcacagccgcccatgccacacaggc cgccctgaatatccaggaaggcctggcttacctgaaccccagcaagcacatgttcaccatcccc aacgtgtacagcccctgcatgggcagcctgagaaccgacctgaccgaagagatccacgtgatga acctgctgtccgccatccccaccagacccggactgaatgaggtgctgcacacccagctggacga gtccgagatcttcgacgccgccttcaagaccatgatgatctttaccacctggaccgccaaggac ctgcacatcctgcacacacacgtgcccgaggtgttcacatgccaagatgccgccgctcggaacg gcgagtatgtgctgattctgcctgccgtgcagggccacagctacgtgatcacccggaacaagcc ccagcggggcctggtgtatagcctggctgacgtggacgtgtacaaccccatcagcgtggtgtac ctgagcaaggatacctgcgtgtccgagcacggcgtgatcgaaacagtggccctgccccaccccg acaacctgaaagagtgcctgtactgcggctccgtgttcctgcggtatctgaccaccggcgccat catggacatcatcatcatcgacagcaaggacaccgagagac agctggccgccatgggcaacagc accatcccccccttcaaccccgacatgcacggcgacgatagcaaggccgtgctgctgttcccca acggcaccgtggtcacactgctgggcttcgagcggagacaggccatcagaatgagcggccagta cctgggcgcctctctgggtggtgcctttctggccgtcgtgggctttggcatcatcggctggatg ctgtgcggcaacagcagactgcgcgagtacaacaagatccccctgacctaatctagacgtcgcg accacccaggatccgcctataactctctacggctaacctgaatggactacgacatagtctagtc gacgccaccatggccagccacaagtggctgctgcagatgatcgtgttcctgaaaaccatcacaa tcgcctactgcctgcatctgcaggacgacacccctctgttcttcggcgccaagcctctgagcga cgtgtccctgatcatcaccgagccttgcgtgtccagcgtgtacgaggcctgggattatgccgcc cctcccgtgtccaatctgagcgaagccctgagcggcatcgtggtcaagaccaagtgccccgtgc ccgaagtgatcctgtggttcaaggacaagcagatggcctactggaccaacccttacgtgaccct gaagggcctgacccagagcgtgggcgaggaacacaagagcggcgacatcagagatgccctgctg gatgccctgtccggtgtctgggtggacagcacaccctccagcaccaacatccccgagaacggct gtgtgtggggagccgaccggctgttccagagagtgtgtcagtaatctagacgcggccgcataca gcagcaattggcaagctgcttacatagaactcgcggcgattggcatgccgccttaaaattttta the ttttatttttcttttcttttccgaatcggattttgtttttaatatttcaaaaaaaaaaaaaaaa aaaaaaaaaaaaaaaaaagggtcggcatggcatctccacctcctcgcggtccgacctgggcat ccgaaggaggacgcacgtccactcggatggctaagggagagccacgtttaaaccagctccaatt cgccctatagtgagtcgtattacgcgcgctcactggccgtcgttttacaacgtcgtgactggga aaaccctggcgttacccaacttaatcgccttgcagcacatccccctttcgccagctggcgtaat agcgaagaggcccgcaccgatcgcccttcccaacagttgcgcagcctgaatggcgaatgggacg cgccctgtagcggcgcattaagcgcggcgggtgtggtggttacgcgcagcgtgaccgctacact tgccagcgccctagcgcccgctcctttcgctttcttcccttcctttctcgccacgttcgccggc tttccccgtcaagctctaaatcgggggctccctttagggttccgatttagtgctttacggcacc tcgaccccaaaaaacttgattagggtgatggttcacgtagtgggccatcgccctgatagacggt ttttcgccctttgacgttggagtccacgttctttaatagtggactcttgttccaaactggaaca acactcaaccctatctcggtctattcttttgatttataagggattttgccgatttcggcctatt ggttaaaaaatgagctgatttaacaaaaatttaacgcgaattttaacaaaatattaacgcttac aatttaggtggcacttttcggggaaatgtgcgcggaacccctatttgtttatttttctaaatac attcaaatatgtatccgctcatgagacaataaccctgataaatgcttcaataatattgaaaaag gaagagtatgagtattcaacatttccgtgtcgcccttattcccttttttgcggcattttgcctt cctgtttttgctcacccagaaacgct ggtgaaagtaaaagatgctgaagatcagttgggtgcac gagtgggttacatcgaactggatctcaacagcggtaagatccttgagagttttcgccccgaaga acgttttccaatgatgagcacttttaaagttctgctatgtggcgcggtattatcccgtattgac gccgggcaagagcaactcggtcgccgcatacactattctcagaatgacttggttgagtactcac cagtcacagaaaagcatcttacggatggcatgacagtaagagaattatgcagtgctgccataac catgagtgataacactgcggccaacttacttctgacaacgatcggaggaccgaaggagctaacc gcttttttgcacaacatgggggatcatgtaactcgccttgatcgttgggaaccggagctgaatg aagccataccaaacgacgagcgtgacaccacgatgcctgtagcaatggcaacaacgttgcgcaa actattaactggcgaactacttactctagcttcccggcaacaattaatagactggatggaggcg gataaagttgcaggaccacttctgcgctcggcccttccggctggctggtttattgctgataaat ctggagccggtgagcgtgggtctcgcggtatcattgcagcactggggccagatggtaagccctc ccgtatcgtagttatctacacgacggggagtcaggcaactatggatgaacgaaatagacagatc gctgagataggtgcctcactgattaagcattggtaactgtcagaccaagtttactcatatatac tttagattgatttaaaacttcatttttaatttaaaaggatctaggtgaagatcctttttgataa tctcatgaccaaaatcccttaacgtgagttttcgttccactgagcgtcagaccccgtagaaaag atcaaaggatcttcttgagatcctttttttctgcgcgtaatctgctgcttg caaacaaaaaaac caccgctaccagcggtggtttgtttgccggatcaagagctaccaactctttttccgaaggtaac tggcttcagcagagcgcagataccaaatactgttcttctagtgtagccgtagttaggccaccac ttcaagaactctgtagcaccgcctacatacctcgctctgctaatcctgttaccagtggctgctg ccagtggcgataagtcgtgtcttaccgggttggactcaagacgatagttaccggataaggcgca gcggtcgggctgaacggggggttcgtgcacacagcccagcttggagcgaacgacctacaccgaa ctgagatacctacagcgtgagctatgagaaagcgccacgcttcccgaagggagaaaggcggaca ggtatccggtaagcggcagggtcggaacaggagagcgcacgagggagcttccagggggaaacgc ctggtatctttatagtcctgtcgggtttcgccacctctgacttgagcgtcgatttttgtgatgc tcgtcaggggggcggagcctatggaaaaacgccagcaacgcggcctttttacggttcctggcct tttgctggccttttgctcacatgttctttcctgcgttatcccctgattctgtggataaccgtat taccgcctttgagtgagctgataccgctcgccgcagccgaacgaccgagcgcagcgagtcagtg agcgaggaagcggaagagcgcccaatacgcaaaccgcctctccccgcgcgttggccgattcatt aatgcagctggcacgacaggtttcccgactggaaagcgggcagtgagcgcaacgcaattaatgt gagttagctcactcattaggcaccccaggctttacactttatgctcccggctcgtatgttgtgt ggaattgtgagcggataacaatttcacacaggaaacagctatgaccatgattacgccaagcgcg caattaaccct cactaaagggaacaaaagctgggtaccgggcccacgcgtaatacgactcacta tag_13827 VZV VEERep. SGPgE 1_ataggcggcgcatgagagaagcccagaccaattacctacccaaaatggagaaagttcacgttga catcgaggaagacagcccattcctcagagctttgcagcggagcttcccgcagtttgaggtagaa gccaagcaggtcactgataatgaccatgctaatgccagagcgttttcgcatctggcttcaaaac tgatcgaaacggaggtggacccatccgacacgatccttgacattggaagtgcgcccgcccgcag aatgtattctaagcacaagtatcattgtatctgtccgatgagatgtgcggaagatccggacaga ttgtataagtatgcaactaagctgaagaaaaactgtaaggaaataactgataaggaattggaca agaaaatgaaggagctcgccgccgtcatgagcgaccctgacctggaaactgagactatgtgcct ccacgacgacgagtcgtgtcgctacgaagggcaagtcgctgtttaccaggatgtatacgcggtt gacggaccgacaagtctctatcaccaagccaataagggagttagagtcgcctactggataggct ttgacaccaccccttttatgtttaagaacttggctggagcatatccatcatactctaccaactg ggccgacgaaaccgtgttaacggctcgtaacataggcctatgcagctctgacgttatggagcgg tcacgtagagggatgtccattcttagaaagaagtatttgaaaccatccaacaatgttctattct ctgttggctcgaccatctaccacgagaagagggacttactgaggagctggcacctgccgtctgt atttcacttacgtggcaagcaaaattacacatgtcggtgtgagactatagttagttgcgacggg tacgtcgttaaaagaatagctatcagtccaggcctgtatgggaagccttcaggctatgctgcta cgatgcaccgcgaggga ttcttgtgctgcaaagtgacagacacattgaacggggagagggtctc ttttcccgtgtgcacgtatgtgccagctacattgtgtgaccaaatgactggcatactggcaaca gatgtcagtgcggacgacgcgcaaaaactgctggttgggctcaaccagcgtatagtcgtcaacg gtcgcacccagagaaacaccaataccatgaaaaattaccttttgcccgtagtggcccaggcatt tgctaggtgggcaaaggaatataaggaagatcaagaagatgaaaggccactaggactacgagat agacagttagtcatggggtgttgttgggcttttagaaggcacaagataacatctatttataagc gcccggatacccaaaccatcatcaaagtgaacagcgatttccactcattcgtgctgcccaggat aggcagtaacacattggagatcgggctgagaacaagaatcaggaaaatgttagaggagcacaag gagccgtcacctctcattaccgccgaggacgtacaagaagctaagtgcgcagccgatgaggcta aggaggtgcgtgaagccgaggagttgcgcgcagctctaccacctttggcagctgatgttgagga gcccactctggaagccgatgtagacttgatgttacaagaggctggggccggctcagtggagaca cctcgtggcttgataaaggttaccagctacgatggcgaggacaagatcggctcttacgctgtgc tttctccgcaggctgtactcaagagtgaaaaattatcttgcatccaccctctcgctgaacaagt catagtgataacacactctggccgaaaagggcgttatgccgtggaaccataccatggtaaagta gtggtgccagagggacatgcaatacccgtccaggactttcaagctctgagtgaaagtgccacca ttgtgtacaacgaacgtgagttcgtaaacaggtacctgcacc atattgccacacatggaggagc gctgaacactgatgaagaatattacaaaactgtcaagcccagcgagcacgacggcgaatacctg tacgacatcgacaggaaacagtgcgtcaagaaagaactagtcactgggctagggctcacaggcg agctggtggatcctcccttccatgaattcgcctacgagagtctgagaacacgaccagccgctcc ttaccaagtaccaaccataggggtgtatggcgtgccaggatcaggcaagtctggcatcattaaa agcgcagtcaccaaaaaagatctagtggtgagcgccaagaaagaaaactgtgcagaaattataa gggacgtcaagaaaatgaaagggctggacgtcaatgccagaactgtggactcagtgctcttgaa tggatgcaaacaccccgtagagaccctgtatattgacgaagcttttgcttgtcatgcaggtact ctcagagcgctcatagccattataagacctaaaaaggcagtgctctgcggggatcccaaacagt gcggtttttttaacatgatgtgcctgaaagtgcattttaaccacgagatttgcacacaagtctt ccacaaaagcatctctcgccgttgcactaaatctgtgacttcggtcgtctcaaccttgttttac gacaaaaaaatgagaacgacgaatccgaaagagactaagattgtgattgacactaccggcagta ccaaacctaagcaggacgatctcattctcacttgtttcagagggtgggtgaagcagttgcaaat agattacaaaggcaacgaaataatgacggcagctgcctctcaagggctgacccgtaaaggtgtg tatgccgttcggtacaaggtgaatgaaaatcctctgtacgcacccacctcagaacatgtgaacg aa tcctactgacccgcacggaggaccgcatcgtgtggaaaacactagccggcgacccatggataaa cactgactgccaagtaccctgggaatttcactgccacgatagaggagtggcaagcagagcat gatgccatcatgaggcacatcttggagagaccggaccctaccgacgtcttccagaataaggcaa acgtgtgttgggccaaggctttagtgccggtgctgaagaccgctggcatagacatgaccactga acaatggaacactgtggattattttgaaacggacaaagctcactcagcagagatagtattgaac caactatgcgtgaggttctttggactcgatctggactccggtctattttctgcacccactgttc cgttatccattaggaataatcactgggataactccccgtcgcctaacatgtacgggctgaataa agaagtggtccgtcagctctctcgcaggtacccacaactgcctcgggcagttgccactggaaga gtctatgacatgaacactggtacactgcgcaattatgatccgcgcataaacctagtacctgtaa acagaagactgcctcatgctttagtcctccaccataatgaacacccacagagtgacttttcttc attcgtcagcaaattgaagggcagaactgtcctggtggtcggggaaaagttgtccgtcccaggc aaaatggttgactggttgtcagaccggcctgaggctaccttcagagctcggctggatttaggca tcccaggtgatgtgcccaaatatgacataatatttgttaatgtgaggaccccatataaatacca tcactatcagcagtgtgaagaccatgccattaagcttagcatgttgaccaagaaagcttgtctg catctgaatcccggcggaacctgtgtcagcataggttatggttacgctgacagggccagcgaaa gcatcattggtgctatagcgcggcagttcaagttttcccgggtatgcaaaccgaaatcctcact tgaagagacggaagttctgtttgtatt cattgggtacgatcgcaaggcccgtacgcacaatcct tacaagctttcatcaaccttgaccaacatttatacaggttccagactccacgaagccggatgtg caccctcatatcatgtggtgcgaggggatattgccacggccaccgaaggagtgattataaatgc tgctaacagcaaaggacaacctggcggaggggtgtgcggagcgctgtataagaaattcccggaa agcttcgatttacagccgatcgaagtaggaaaagcgcgactggtcaaaggtgcagctaaacata tcattcatgccgtaggaccaaacttcaacaaagtttcggaggttgaaggtgacaaacagttggc agaggcttatgagtccatcgctaagattgtcaacgataacaattacaagtcagtagcgattcca ctgttgtccaccggcatcttttccgggaacaaagatcgactaacccaatcattgaaccatttgc tgacagctttagacaccactgatgcagatgtagccatatactgcagggacaagaaatgggaaat gactctcaaggaagcagtggctaggagagaagcagtggaggagatatgcatatccgacgactct tcagtgacagaacctgatgcagagctggtgagggtgcatccgaagagttctttggctggaagga agggctacagcacaagcgatggcaaaactttctcatatttggaagggaccaagtttcaccaggc ggccaaggatatagcagaaattaatgccatgtggcccgttgcaacggaggccaatgagcaggta tgcatgtatatcctcggagaaagcatgagcagtattaggtcgaaatgccccgtcgaagagtcgg aagcctccacaccacctagcacgctgccttgcttgtgcatccatgccatgactccagaaagagt acagcgcctaaaagcctcacgtccagaacaaattactgtgtgctcatccttt ccattgccgaag tatagaatcactggtgtgcagaagatccaatgctcccagcctatattgttctcaccgaaagtgc ctgcgtatattcatccaaggaagtatctcgtggaaacaccaccggtagacgagactccggagcc atcggcagagaaccaatccacagaggggacacctgaacaaccaccacttataaccgaggatgag accaggactagaacgcctgagccgatcatcatcgaagaggaagaagaggatagcataagtttgc tgtcagatggcccgacccaccaggtgctgcaagtcgaggcagacattcacgggccgccctctgt atctagctcatcctggtccattcctcatgcatccgactttgatgtggacagtttatccatactt gacaccctggagggagctagcgtgaccagcggggcaacgtcagccgagactaactcttacttcg caaagagtatggagtttctggcgcgaccggtgcctgcgcctcgaacagtattcaggaaccctcc acatcccgctccgcgcacaagaacaccgtcacttgcacccagcagggcctgctcgagaaccagc ctagtttccaccccgccaggcgtgaatagggtgatcactagagaggagctcgaggcgcttaccc cgtcacgcactcctagcaggtcggtctcgagaaccagcctggtctccaacccgccaggcgtaaa tagggtgattacaagagaggagtttgaggcgttcgtagcacaacaacaatgacggtttgatgcg ggtgcatacatcttttcctccgacaccggtcaagggcatttacaacaaaaatcagtaaggcaaa cggtgctatccgaagtggtgttggagaggaccgaattggagatttcgtatgccccgcgcctcga ccaagaaaaagaagaattactacgcaagaaattacagttaaatcccacacctgctaacagaagc agataccagtcc aggaaggtggagaacatgaaagccataacagctagacgtattctgcaaggcc tagggcattatttgaaggcagaaggaaaagtggagtgctaccgaaccctgcatcctgttccttt gtattcatctagtgtgaaccgtgccttttcaagccccaaggtcgcagtggaagcctgtaacgcc atgttgaaagagaactttccgactgtggcttcttactgtattattccagagtacgatgcctatt tggacatggttgacggagcttcatgctgcttagacactgccagtttttgccctgcaaagctgcg cagctttccaaagaaacactcctatttggaacccacaatacgatcggcagtgccttcagcgatc cagaacacgctccagaacgtcctggcagctgccacaaaaagaaattgcaatgtcacgcaaatga gagaattgcccgtattggattcggcggcctttaatgtggaatgcttcaagaaatatgcgtgtaa taatgaatattgggaaacgtttaaagaaaaccccatcaggcttactgaagaaaacgtggtaaat tacattaccaaattaaaaggaccaaaagctgctgctctttttgcgaagacacataatttgaata tgttgcaggacataccaatggacaggtttgtaatggacttaaagagagacgtgaaagtgactcc aggaacaaaacatactgaagaacggcccaaggtacaggtgatccaggctgccgatccgctagca acagcgtatctgtgcggaatccaccgagagctggttaggagattaaatgcggtcctgcttccga acattcatacactgtttgatatgtcggctgaagactttgacgctattatagccgagcacttcca gcctggggattgtgttctggaaactgacatcgcgtcgtttgataaaagtgaggacgacgccatg gctctgaccgcgttaatgattctggaagacttaggtg tggacgcagagctgttgacgctgattg aggcggctttcggcgaaatttcatcaatacatttgcccactaaaactaaatttaaattcggagc catgatgaaatctggaatgttcctcacactgtttgtgaacacagtcattaacattgtaatcgca agcagagtgttgagagaacggctaaccggatcaccatgtgcagcattcattggagatgacaata tcgtgaaaggagtcaaatcggacaaattaatggcagacaggtgcgccacctggttgaatatgga agtcaagattatagatgctgtggtgggcgagaaagcgccttatttctgtggagggtttattttg tgtgactccgtgaccggcacagcgtgccgtgtggcagaccccctaaaaaggctgtttaagcttg gcaaacctctggcagcagacgatgaacatgatgatgacaggagaagggcattgcatgaagagtc aacacgctggaaccgagtgggtattctttcagagctgtgcaaggcagtagaatcaaggtatgaa accgtaggaacttccatcatagttatggccatgactactctagctagcagtgttaaatcattca gctacctgagaggggcccctataactctctacggctaacctgaatggactacgacatagtctag tcgagtctagtcgacgccaccatgggcaccgtgaacaagcctgtcgtgggcgtgctgatgggct tcggcatcatcaccggcaccctgagaatcaccaaccctgtgcgggccagcgtgctgagatacga cgacttccacatcgacgaggacaagctggacaccaacagcgtgtacgagccctactaccacagc gaccacgccgagagcagctgggtcaacagaggcgagagcagccggaaggcctacgaccacaaca gcccctacatctggccccggaacgactacgacggcttcctggaaaacgcccacgagcaccac gg cgtgtacaatcagggcagaggcatcgacagcggcgagagactgatgcagcccacacagatgagc gcccaggaagatctgggcgacgacacaggcatccacgtgatccccaccctgaacggcgacgacc ggcacaagatcgtgaacgtggaccagcggcagtacggcgacgtgttcaagggcgacctgaaccc taagccccagggccagagactgatcgaggtgtccgtggaagagaaccaccccttcaccctgaga gcccccatccagagaatctacggcgtgcggtataccgagacttggagcttcctgcccagcctga cctgtacaggcgacgccgctcctgccatccagcacatctgcctgaagcacaccacctgtttcca ggacgtggtggtggacgtggactgcgccgagaacaccaaagaggaccagctggccgagatcagc taccggttccagggcaagaaagaggccgaccagccctggatcgtggtcaataccagcaccctgt tcgacgagctggaactggacccccccgagattgaacccggcgtgctgaaggtgctgcggaccga gaagcagtacctgggcgtgtacatctggaacatgcggggctccgacggcacctctacctacgcc accttcctggtcacatggaagggcgacgagaaaacccggaaccctacccctgccgtgacccctc agcctagaggcgccgagttccatatgtggaattaccactcccacgtgttcagcgtgggcgacac cttcagcctggccatgcatctgcagtacaagatccacgaggcccccttcgacctgctgctggaa tggctgtacgtgcccatcgaccctacctgccagcccatgcggctgtacagcacctgtctgtacc accccaacgcccctcagtgcctgagccacatgaacagcggctgcaccttcaccagccctcacct ggctcagagggtggccagcacc gtgtaccagaattgcgagcacgccgacaactacaccgcctac tgcctgggcatcagccacatggaacccagcttcggcctgatcctgcacgatggcggcaccaccc tgaagttcgtggacacacccgagagcctgagcggcctgtacgtgttcgtggtgtacttcaacgg ccacgtggaagccgtggcctacaccgtggtgtccaccgtggaccacttcgtgaacgccatcgag gaaagaggcttcccacccacagccggacagcctccagccaccaccaagcccaaagaaatcaccc ccgtgaaccccggcaccagccccctgctgagatatgctgcttggacaggcggactggccgctgt ggtgctgctgtgcctggtcatcttcctgatctgcaccgccaagcggatgagagtgaaggcctac cgggtggacaagtccccctacaaccagagcatgtactacgccggcctgcccgtggacgatttcg aggatagcgagagcaccgacaccgaggaagagttcggcaacgccatcggcggatctcacggcgg cagcagctacaccgtgtacatcgacaagaccagataatctagacgcggccgcatacagcagcaa ttggcaagctgcttacatagaactcgcggcgattggcatgccgccttaaaatttttattttatt tttcttttcttttccgaatcggattttgtttttaatatttcaaaaaaaaaaaaaaaaaaaaaaa aaaaaaaaaaaagggtcggcatggcatctccacctcctcgcggtccgacctgggcatccgaagg aggacgcacgtccactcggatggctaagggagagccacgtttaaaccagctccaattcgcccta tagtgagtcgtattacgcgcgctcactggccgtcgttttacaacgtcgtgactgggaaaaccct ggcgttacccaacttaatcgccttgcagcacatccccctttcgccag ctggcgtaatagcgaag aggcccgcaccgatcgcccttcccaacagttgcgcagcctgaatggcgaatgggacgcgccctg tagcggcgcattaagcgcggcgggtgtggtggttacgcgcagcgtgaccgctacacttgccagc gccctagcgcccgctcctttcgctttcttcccttcctttctcgccacgttcgccggctttcccc gtcaagctctaaatcgggggctccctttagggttccgatttagtgctttacggcacctcgaccc caaaaaacttgattagggtgatggttcacgtagtgggccatcgccctgatagacggtttttcgc cctttgacgttggagtccacgttctttaatagtggactcttgttccaaactggaacaacactca accctatctcggtctattcttttgatttataagggattttgccgatttcggcctattggttaaa aaatgagctgatttaacaaaaatttaacgcgaattttaacaaaatattaacgcttacaatttag gtggcacttttcggggaaatgtgcgcggaacccctatttgtttatttttctaaatacattcaaa tatgtatccgctcatgagacaataaccctgataaatgcttcaataatattgaaaaaggaagagt atgagtattcaacatttccgtgtcgcccttattcccttttttgcggcattttgccttcctgttt ttgctcacccagaaacgctggtgaaagtaaaagatgctgaagatcagttgggtgcacgagtggg ttacatcgaactggatctcaacagcggtaagatccttgagagttttcgccccgaagaacgtttt ccaatgatgagcacttttaaagttctgctatgtggcgcggtattatcccgtattgacgccgggc aagagcaactcggtcgccgcatacactattctcagaatgacttggttgagtactcaccagtcac agaaaag catcttacggatggcatgacagtaagagaattatgcagtgctgccataaccatgagt gataacactgcggccaacttacttctgacaacgatcggaggaccgaaggagctaaccgcttttt tgcacaacatgggggatcatgtaactcgccttgatcgttgggaaccggagctgaatgaagccat accaaacgacgagcgtgacaccacgatgcctgtagcaatggcaacaacgttgcgcaaactatta actggcgaactacttactctagcttcccggcaacaattaatagactggatggaggcggataaag ttgcaggaccacttctgcgctcggcccttccggctggctggtttattgctgataaatctggagc cggtgagcgtgggtctcgcggtatcattgcagcactggggccagatggtaagccctcccgtatc gtagttatctacacgacggggagtcaggcaactatggatgaacgaaatagacagatcgctgaga taggtgcctcactgattaagcattggtaactgtcagaccaagtttactcatatatactttagat tgatttaaaacttcatttttaatttaaaaggatctaggtgaagatcctttttgataatctcatg accaaaatcccttaacgtgagttttcgttccactgagcgtcagaccccgtagaaaagatcaaag gatcttcttgagatcctttttttctgcgcgtaatctgctgcttgcaaacaaaaaaaccaccgct accagcggtggtttgtttgccggatcaagagctaccaactctttttccgaaggtaactggcttc agcagagcgcagataccaaatactgttcttctagtgtagccgtagttaggccaccacttcaaga actctgtagcaccgcctacatacctcgctctgctaatcctgttaccagtggctgctgccagtgg cgataagtcgtgtcttaccgggttggactcaa gacgatagttaccggataaggcgcagcggtcg ggctgaacggggggttcgtgcacacagcccagcttggagcgaacgacctacaccgaactgagat acctacagcgtgagctatgagaaagcgccacgcttcccgaagggagaaaggcggacaggtatcc ggtaagcggcagggtcggaacaggagagcgcacgagggagcttccagggggaaacgcctggtat ctttatagtcctgtcgggtttcgccacctctgacttgagcgtcgatttttgtgatgctcgtcag gggggcggagcctatggaaaaacgccagcaacgcggcctttttacggttcctggccttttgctg gccttttgctcacatgttctttcctgcgttatcccctgattctgtggataaccgtattaccgcc tttgagtgagctgataccgctcgccgcagccgaacgaccgagcgcagcgagtcagtgagcgagg aagcggaagagcgcccaatacgcaaaccgcctctccccgcgcgttggccgattcattaatgcag ctggcacgacaggtttcccgactggaaagcgggcagtgagcgcaacgcaattaatgtgagttag ctcactcattaggcaccccaggctttacactttatgctcccggctcgtatgttgtgtggaattg tgagcggataacaatttcacacaggaaacagctatgaccatgattacgccaagcgcgcaattaa ccctcactaaagggaacaaaagctgggtaccgggcccacgcgtaatacgactcactatag_126 04 VZV VEERep. SGPGI 1_ataggcggcgcatgagagaagcccagaccaattacctacccaaaatggagaaagttcacgttga catcgaggaagacagcccattcctcagagctttgcagcggagcttcccgcagtttgaggtagaa gccaagcaggtcactgataatgaccatgctaatgccagagcgttttcgcatctggcttcaaaac tgatcgaaacggaggtggacccatccgacacgatccttgacattggaagtgcgcccgcccgcag aatgtattctaagcacaagtatcattgtatctgtccgatgagatgtgcggaagatccggacaga ttgtataagtatgcaactaagctgaagaaaaactgtaaggaaataactgataaggaattggaca agaaaatgaaggagctcgccgccgtcatgagcgaccctgacctggaaactgagactatgtgcct ccacgacgacgagtcgtgtcgctacgaagggcaagtcgctgtttaccaggatgtatacgcggtt gacggaccgacaagtctctatcaccaagccaataagggagttagagtcgcctactggataggct ttgacaccaccccttttatgtttaagaacttggctggagcatatccatcatactctaccaactg ggccgacgaaaccgtgttaacggctcgtaacataggcctatgcagctctgacgttatggagcgg tcacgtagagggatgtccattcttagaaagaagtatttgaaaccatccaacaatgttctattct ctgttggctcgaccatctaccacgagaagagggacttactgaggagctggcacctgccgtctgt atttcacttacgtggcaagcaaaattacacatgtcggtgtgagactatagttagttgcgacggg tacgtcgttaaaagaatagctatcagtccaggcctgtatgggaagccttcaggctatgctgcta cgatgcaccgcgaggga ttcttgtgctgcaaagtgacagacacattgaacggggagagggtctc ttttcccgtgtgcacgtatgtgccagctacattgtgtgaccaaatgactggcatactggcaaca gatgtcagtgcggacgacgcgcaaaaactgctggttgggctcaaccagcgtatagtcgtcaacg gtcgcacccagagaaacaccaataccatgaaaaattaccttttgcccgtagtggcccaggcatt tgctaggtgggcaaaggaatataaggaagatcaagaagatgaaaggccactaggactacgagat agacagttagtcatggggtgttgttgggcttttagaaggcacaagataacatctatttataagc gcccggatacccaaaccatcatcaaagtgaacagcgatttccactcattcgtgctgcccaggat aggcagtaacacattggagatcgggctgagaacaagaatcaggaaaatgttagaggagcacaag gagccgtcacctctcattaccgccgaggacgtacaagaagctaagtgcgcagccgatgaggcta aggaggtgcgtgaagccgaggagttgcgcgcagctctaccacctttggcagctgatgttgagga gcccactctggaagccgatgtagacttgatgttacaagaggctggggccggctcagtggagaca cctcgtggcttgataaaggttaccagctacgatggcgaggacaagatcggctcttacgctgtgc tttctccgcaggctgtactcaagagtgaaaaattatcttgcatccaccctctcgctgaacaagt catagtgataacacactctggccgaaaagggcgttatgccgtggaaccataccatggtaaagta gtggtgccagagggacatgcaatacccgtccaggactttcaagctctgagtgaaagtgccacca ttgtgtacaacgaacgtgagttcgtaaacaggtacctgcacc atattgccacacatggaggagc gctgaacactgatgaagaatattacaaaactgtcaagcccagcgagcacgacggcgaatacctg tacgacatcgacaggaaacagtgcgtcaagaaagaactagtcactgggctagggctcacaggcg agctggtggatcctcccttccatgaattcgcctacgagagtctgagaacacgaccagccgctcc ttaccaagtaccaaccataggggtgtatggcgtgccaggatcaggcaagtctggcatcattaaa agcgcagtcaccaaaaaagatctagtggtgagcgccaagaaagaaaactgtgcagaaattataa gggacgtcaagaaaatgaaagggctggacgtcaatgccagaactgtggactcagtgctcttgaa tggatgcaaacaccccgtagagaccctgtatattgacgaagcttttgcttgtcatgcaggtact ctcagagcgctcatagccattataagacctaaaaaggcagtgctctgcggggatcccaaacagt gcggtttttttaacatgatgtgcctgaaagtgcattttaaccacgagatttgcacacaagtctt ccacaaaagcatctctcgccgttgcactaaatctgtgacttcggtcgtctcaaccttgttttac gacaaaaaaatgagaacgacgaatccgaaagagactaagattgtgattgacactaccggcagta ccaaacctaagcaggacgatctcattctcacttgtttcagagggtgggtgaagcagttgcaaat agattacaaaggcaacgaaataatgacggcagctgcctctcaagggctgacccgtaaaggtgtg tatgccgttcggtacaaggtgaatgaaaatcctctgtacgcacccacctcagaacatgtgaacg aa tcctactgacccgcacggaggaccgcatcgtgtggaaaacactagccggcgacccatggataaa cactgactgccaagtaccctgggaatttcactgccacgatagaggagtggcaagcagagcat gatgccatcatgaggcacatcttggagagaccggaccctaccgacgtcttccagaataaggcaa acgtgtgttgggccaaggctttagtgccggtgctgaagaccgctggcatagacatgaccactga acaatggaacactgtggattattttgaaacggacaaagctcactcagcagagatagtattgaac caactatgcgtgaggttctttggactcgatctggactccggtctattttctgcacccactgttc cgttatccattaggaataatcactgggataactccccgtcgcctaacatgtacgggctgaataa agaagtggtccgtcagctctctcgcaggtacccacaactgcctcgggcagttgccactggaaga gtctatgacatgaacactggtacactgcgcaattatgatccgcgcataaacctagtacctgtaa acagaagactgcctcatgctttagtcctccaccataatgaacacccacagagtgacttttcttc attcgtcagcaaattgaagggcagaactgtcctggtggtcggggaaaagttgtccgtcccaggc aaaatggttgactggttgtcagaccggcctgaggctaccttcagagctcggctggatttaggca tcccaggtgatgtgcccaaatatgacataatatttgttaatgtgaggaccccatataaatacca tcactatcagcagtgtgaagaccatgccattaagcttagcatgttgaccaagaaagcttgtctg catctgaatcccggcggaacctgtgtcagcataggttatggttacgctgacagggccagcgaaa gcatcattggtgctatagcgcggcagttcaagttttcccgggtatgcaaaccgaaatcctcact tgaagagacggaagttctgtttgtatt cattgggtacgatcgcaaggcccgtacgcacaatcct tacaagctttcatcaaccttgaccaacatttatacaggttccagactccacgaagccggatgtg caccctcatatcatgtggtgcgaggggatattgccacggccaccgaaggagtgattataaatgc tgctaacagcaaaggacaacctggcggaggggtgtgcggagcgctgtataagaaattcccggaa agcttcgatttacagccgatcgaagtaggaaaagcgcgactggtcaaaggtgcagctaaacata tcattcatgccgtaggaccaaacttcaacaaagtttcggaggttgaaggtgacaaacagttggc agaggcttatgagtccatcgctaagattgtcaacgataacaattacaagtcagtagcgattcca ctgttgtccaccggcatcttttccgggaacaaagatcgactaacccaatcattgaaccatttgc tgacagctttagacaccactgatgcagatgtagccatatactgcagggacaagaaatgggaaat gactctcaaggaagcagtggctaggagagaagcagtggaggagatatgcatatccgacgactct tcagtgacagaacctgatgcagagctggtgagggtgcatccgaagagttctttggctggaagga agggctacagcacaagcgatggcaaaactttctcatatttggaagggaccaagtttcaccaggc ggccaaggatatagcagaaattaatgccatgtggcccgttgcaacggaggccaatgagcaggta tgcatgtatatcctcggagaaagcatgagcagtattaggtcgaaatgccccgtcgaagagtcgg aagcctccacaccacctagcacgctgccttgcttgtgcatccatgccatgactccagaaagagt acagcgcctaaaagcctcacgtccagaacaaattactgtgtgctcatccttt ccattgccgaag tatagaatcactggtgtgcagaagatccaatgctcccagcctatattgttctcaccgaaagtgc ctgcgtatattcatccaaggaagtatctcgtggaaacaccaccggtagacgagactccggagcc atcggcagagaaccaatccacagaggggacacctgaacaaccaccacttataaccgaggatgag accaggactagaacgcctgagccgatcatcatcgaagaggaagaagaggatagcataagtttgc tgtcagatggcccgacccaccaggtgctgcaagtcgaggcagacattcacgggccgccctctgt atctagctcatcctggtccattcctcatgcatccgactttgatgtggacagtttatccatactt gacaccctggagggagctagcgtgaccagcggggcaacgtcagccgagactaactcttacttcg caaagagtatggagtttctggcgcgaccggtgcctgcgcctcgaacagtattcaggaaccctcc acatcccgctccgcgcacaagaacaccgtcacttgcacccagcagggcctgctcgagaaccagc ctagtttccaccccgccaggcgtgaatagggtgatcactagagaggagctcgaggcgcttaccc cgtcacgcactcctagcaggtcggtctcgagaaccagcctggtctccaacccgccaggcgtaaa tagggtgattacaagagaggagtttgaggcgttcgtagcacaacaacaatgacggtttgatgcg ggtgcatacatcttttcctccgacaccggtcaagggcatttacaacaaaaatcagtaaggcaaa cggtgctatccgaagtggtgttggagaggaccgaattggagatttcgtatgccccgcgcctcga ccaagaaaaagaagaattactacgcaagaaattacagttaaatcccacacctgctaacagaagc agataccagtcc aggaaggtggagaacatgaaagccataacagctagacgtattctgcaaggcc tagggcattatttgaaggcagaaggaaaagtggagtgctaccgaaccctgcatcctgttccttt gtattcatctagtgtgaaccgtgccttttcaagccccaaggtcgcagtggaagcctgtaacgcc atgttgaaagagaactttccgactgtggcttcttactgtattattccagagtacgatgcctatt tggacatggttgacggagcttcatgctgcttagacactgccagtttttgccctgcaaagctgcg cagctttccaaagaaacactcctatttggaacccacaatacgatcggcagtgccttcagcgatc cagaacacgctccagaacgtcctggcagctgccacaaaaagaaattgcaatgtcacgcaaatga gagaattgcccgtattggattcggcggcctttaatgtggaatgcttcaagaaatatgcgtgtaa taatgaatattgggaaacgtttaaagaaaaccccatcaggcttactgaagaaaacgtggtaaat tacattaccaaattaaaaggaccaaaagctgctgctctttttgcgaagacacataatttgaata tgttgcaggacataccaatggacaggtttgtaatggacttaaagagagacgtgaaagtgactcc aggaacaaaacatactgaagaacggcccaaggtacaggtgatccaggctgccgatccgctagca acagcgtatctgtgcggaatccaccgagagctggttaggagattaaatgcggtcctgcttccga acattcatacactgtttgatatgtcggctgaagactttgacgctattatagccgagcacttcca gcctggggattgtgttctggaaactgacatcgcgtcgtttgataaaagtgaggacgacgccatg gctctgaccgcgttaatgattctggaagacttaggtg tggacgcagagctgttgacgctgattg aggcggctttcggcgaaatttcatcaatacatttgcccactaaaactaaatttaaattcggagc catgatgaaatctggaatgttcctcacactgtttgtgaacacagtcattaacattgtaatcgca agcagagtgttgagagaacggctaaccggatcaccatgtgcagcattcattggagatgacaata tcgtgaaaggagtcaaatcggacaaattaatggcagacaggtgcgccacctggttgaatatgga agtcaagattatagatgctgtggtgggcgagaaagcgccttatttctgtggagggtttattttg tgtgactccgtgaccggcacagcgtgccgtgtggcagaccccctaaaaaggctgtttaagcttg gcaaacctctggcagcagacgatgaacatgatgatgacaggagaagggcattgcatgaagagtc aacacgctggaaccgagtgggtattctttcagagctgtgcaaggcagtagaatcaaggtatgaa accgtaggaacttccatcatagttatggccatgactactctagctagcagtgttaaatcattca gctacctgagaggggcccctataactctctacggctaacctgaatggactacgacatagtctag tcgagtctagtcgacgccaccatgtttctgatccagtgcctgatcagcgccgtgatcttctata ttcaagtcacaaacgccctgatctttaagggcgaccacgtgtcactgcaggtcaacagcagcct gaccagcatcctgatccccatgcagaacgacaattacaccgagatcaagggccagctggtgttc atcggcgagcagctgcccaccggcaccaattacagcggcaccctggaactgctgtacgccgata ccgtggccttctgcttcagaagcgtgcaggtcatcagatacgacggctgcccccggatcaga ac cagcgccttcatcagctgccggtacaagcacagctggcactacggcaacagcaccgaccggatc agcaccgaacctgatgccggcgtgatgctgaagatcaccaagcccggcatcaacgacgccggcg tgtacgtgctgctcgtgcggctggatcacagcagaagcaccgacggcttcatcctgggcgtgaa cgtgtacaccgccggcagccaccacaacatccacggcgtgatctacaccagccccagcctgcag aacggctacagcaccagagccctgttccagcaggccagactgtgcgatctgcccgccacaccta agggcagcggcacaagcctgtttcagcacatgctggacctgagagccggcaagagcctggaaga taacccctggctgcacgaggacgtggtcaccaccgagacaaagagcgtggtcaaagagggcatc gagaaccacgtgtaccccaccgacatgagcaccctgcccgagaagtccctgaacgacccccctg agaacctgctgatcatcatccccatcgtggccagcgtgatgatcctgaccgccatggtcatcgt gatcgtgatcagcgtgaagcggcggagaatcaagaagcaccccatctaccggcccaacaccaag accagacggggcatccagaacgccacccctgagtccgacgtgatgctggaagccgccattgccc agctggccaccatcagagaggaaagcccccctcacagcgtcgtgaaccccttcgtgaagtaatc tagacgcggccgcatacagcagcaattggcaagctgcttacatagaactcgcggcgattggcat gccgccttaaaatttttattttatttttcttttcttttccgaatcggattttgtttttaatatt tcaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaagggtcggcatggcatctccacctcctc gcggtccgacctgggcatccga aggaggacgcacgtccactcggatggctaagggagagccacg tttaaaccagctccaattcgccctatagtgagtcgtattacgcgcgctcactggccgtcgtttt acaacgtcgtgactgggaaaaccctggcgttacccaacttaatcgccttgcagcacatccccct ttcgccagctggcgtaatagcgaagaggcccgcaccgatcgcccttcccaacagttgcgcagcc tgaatggcgaatgggacgcgccctgtagcggcgcattaagcgcggcgggtgtggtggttacgcg cagcgtgaccgctacacttgccagcgccctagcgcccgctcctttcgctttcttcccttccttt ctcgccacgttcgccggctttccccgtcaagctctaaatcgggggctccctttagggttccgat ttagtgctttacggcacctcgaccccaaaaaacttgattagggtgatggttcacgtagtgggcc atcgccctgatagacggtttttcgccctttgacgttggagtccacgttctttaatagtggactc ttgttccaaactggaacaacactcaaccctatctcggtctattcttttgatttataagggattt tgccgatttcggcctattggttaaaaaatgagctgatttaacaaaaatttaacgcgaattttaa caaaatattaacgcttacaatttaggtggcacttttcggggaaatgtgcgcggaacccctattt gtttatttttctaaatacattcaaatatgtatccgctcatgagacaataaccctgataaatgct tcaataatattgaaaaaggaagagtatgagtattcaacatttccgtgtcgcccttattcccttt tttgcggcattttgccttcctgtttttgctcacccagaaacgctggtgaaagtaaaagatgctg aagatcagttgggtgcacgagtgggttacatcgaactggatctcaac agcggtaagatccttga gagttttcgccccgaagaacgttttccaatgatgagcacttttaaagttctgctatgtggcgcg gtattatcccgtattgacgccgggcaagagcaactcggtcgccgcatacactattctcagaatg acttggttgagtactcaccagtcacagaaaagcatcttacggatggcatgacagtaagagaatt atgcagtgctgccataaccatgagtgataacactgcggccaacttacttctgacaacgatcgga ggaccgaaggagctaaccgcttttttgcacaacatgggggatcatgtaactcgccttgatcgtt gggaaccggagctgaatgaagccataccaaacgacgagcgtgacaccacgatgcctgtagcaat ggcaacaacgttgcgcaaactattaactggcgaactacttactctagcttcccggcaacaatta atagactggatggaggcggataaagttgcaggaccacttctgcgctcggcccttccggctggct ggtttattgctgataaatctggagccggtgagcgtgggtctcgcggtatcattgcagcactggg gccagatggtaagccctcccgtatcgtagttatctacacgacggggagtcaggcaactatggat gaacgaaatagacagatcgctgagataggtgcctcactgattaagcattggtaactgtcagacc aagtttactcatatatactttagattgatttaaaacttcatttttaatttaaaaggatctaggt gaagatcctttttgataatctcatgaccaaaatcccttaacgtgagttttcgttccactgagcg tcagaccccgtagaaaagatcaaaggatcttcttgagatcctttttttctgcgcgtaatctgct gcttgcaaacaaaaaaaccaccgctaccagcggtggtttgtttgccggatcaagagctaccaac tcttttt ccgaaggtaactggcttcagcagagcgcagataccaaatactgttcttctagtgtag ccgtagttaggccaccacttcaagaactctgtagcaccgcctacatacctcgctctgctaatcc tgttaccagtggctgctgccagtggcgataagtcgtgtcttaccgggttggactcaagacgata gttaccggataaggcgcagcggtcgggctgaacggggggttcgtgcacacagcccagcttggag cgaacgacctacaccgaactgagatacctacagcgtgagctatgagaaagcgccacgcttcccg aagggagaaaggcggacaggtatccggtaagcggcagggtcggaacaggagagcgcacgaggga gcttccagggggaaacgcctggtatctttatagtcctgtcgggtttcgccacctctgacttgag cgtcgatttttgtgatgctcgtcaggggggcggagcctatggaaaaacgccagcaacgcggcct ttttacggttcctggccttttgctggccttttgctcacatgttctttcctgcgttatcccctga ttctgtggataaccgtattaccgcctttgagtgagctgataccgctcgccgcagccgaacgacc gagcgcagcgagtcagtgagcgaggaagcggaagagcgcccaatacgcaaaccgcctctccccg cgcgttggccgattcattaatgcagctggcacgacaggtttcccgactggaaagcgggcagtga gcgcaacgcaattaatgtgagttagctcactcattaggcaccccaggctttacactttatgctc ccggctcgtatgttgtgtggaattgtgagcggataacaatttcacacaggaaacagctatgacc atgattacgccaagcgcgcaattaaccctcactaaagggaacaaaagctgggtaccgggcccac gcgtaatacgactcactatag_11797 VZV VEErep. SGPgE-SGPGI 1_ataggcggcgcatgagagaagcccagaccaattacctacccaaaatggagaaagttcacgttga catcgaggaagacagcccattcctcagagctttgcagcggagcttcccgcagtttgaggtagaa gccaagcaggtcactgataatgaccatgctaatgccagagcgttttcgcatctggcttcaaaac tgatcgaaacggaggtggacccatccgacacgatccttgacattggaagtgcgcccgcccgcag aatgtattctaagcacaagtatcattgtatctgtccgatgagatgtgcggaagatccggacaga ttgtataagtatgcaactaagctgaagaaaaactgtaaggaaataactgataaggaattggaca agaaaatgaaggagctcgccgccgtcatgagcgaccctgacctggaaactgagactatgtgcct ccacgacgacgagtcgtgtcgctacgaagggcaagtcgctgtttaccaggatgtatacgcggtt gacggaccgacaagtctctatcaccaagccaataagggagttagagtcgcctactggataggct ttgacaccaccccttttatgtttaagaacttggctggagcatatccatcatactctaccaactg ggccgacgaaaccgtgttaacggctcgtaacataggcctatgcagctctgacgttatggagcgg tcacgtagagggatgtccattcttagaaagaagtatttgaaaccatccaacaatgttctattct ctgttggctcgaccatctaccacgagaagagggacttactgaggagctggcacctgccgtctgt atttcacttacgtggcaagcaaaattacacatgtcggtgtgagactatagttagttgcgacggg tacgtcgttaaaagaatagctatcagtccaggcctgtatgggaagccttcaggctatgctgcta cgatgcaccgc gagggattcttgtgctgcaaagtgacagacacattgaacggggagagggtctc ttttcccgtgtgcacgtatgtgccagctacattgtgtgaccaaatgactggcatactggcaaca gatgtcagtgcggacgacgcgcaaaaactgctggttgggctcaaccagcgtatagtcgtcaacg gtcgcacccagagaaacaccaataccatgaaaaattaccttttgcccgtagtggcccaggcatt tgctaggtgggcaaaggaatataaggaagatcaagaagatgaaaggccactaggactacgagat agacagttagtcatggggtgttgttgggcttttagaaggcacaagataacatctatttataagc gcccggatacccaaaccatcatcaaagtgaacagcgatttccactcattcgtgctgcccaggat aggcagtaacacattggagatcgggctgagaacaagaatcaggaaaatgttagaggagcacaag gagccgtcacctctcattaccgccgaggacgtacaagaagctaagtgcgcagccgatgaggcta aggaggtgcgtgaagccgaggagttgcgcgcagctctaccacctttggcagctgatgttgagga gcccactctggaagccgatgtagacttgatgttacaagaggctggggccggctcagtggagaca cctcgtggcttgataaaggttaccagctacgatggcgaggacaagatcggctcttacgctgtgc tttctccgcaggctgtactcaagagtgaaaaattatcttgcatccaccctctcgctgaacaagt catagtgataacacactctggccgaaaagggcgttatgccgtggaaccataccatggtaaagta gtggtgccagagggacatgcaatacccgtccaggactttcaagctctgagtgaaagtgccacca ttgtgtacaacgaacgtgagttcgtaaacaggtacc tgcaccatattgccacacatggaggagc gctgaacactgatgaagaatattacaaaactgtcaagcccagcgagcacgacggcgaatacctg tacgacatcgacaggaaacagtgcgtcaagaaagaactagtcactgggctagggctcacaggcg agctggtggatcctcccttccatgaattcgcctacgagagtctgagaacacgaccagccgctcc ttaccaagtaccaaccataggggtgtatggcgtgccaggatcaggcaagtctggcatcattaaa agcgcagtcaccaaaaaagatctagtggtgagcgccaagaaagaaaactgtgcagaaattataa gggacgtcaagaaaatgaaagggctggacgtcaatgccagaactgtggactcagtgctcttgaa tggatgcaaacaccccgtagagaccctgtatattgacgaagcttttgcttgtcatgcaggtact ctcagagcgctcatagccattataagacctaaaaaggcagtgctctgcggggatcccaaacagt gcggtttttttaacatgatgtgcctgaaagtgcattttaaccacgagatttgcacacaagtctt ccacaaaagcatctctcgccgttgcactaaatctgtgacttcggtcgtctcaaccttgttttac gacaaaaaaatgagaacgacgaatccgaaagagactaagattgtgattgacactaccggcagta ccaaacctaagcaggacgatctcattctcacttgtttcagagggtgggtgaagcagttgcaaat agattacaaaggcaacgaaataatgacggcagctgcctctcaagggctgacccgtaaaggtgtg tatgccgttcggtacaaggtgaatgaaaatcctctgtacgcacccacctcagaacatgtgaacg tcctactgacccgcacggaggaccgcatcgtgtggaaaacactagccggcgacccatggat aaa aacactgactgccaagtaccctgggaatttcactgccacgatagaggagtggcaagcagagcat gatgccatcatgaggcacatcttggagagaccggaccctaccgacgtcttccagaataaggcaa acgtgtgttgggccaaggctttagtgccggtgctgaagaccgctggcatagacatgaccactga acaatggaacactgtggattattttgaaacggacaaagctcactcagcagagatagtattgaac caactatgcgtgaggttctttggactcgatctggactccggtctattttctgcacccactgttc cgttatccattaggaataatcactgggataactccccgtcgcctaacatgtacgggctgaataa agaagtggtccgtcagctctctcgcaggtacccacaactgcctcgggcagttgccactggaaga gtctatgacatgaacactggtacactgcgcaattatgatccgcgcataaacctagtacctgtaa acagaagactgcctcatgctttagtcctccaccataatgaacacccacagagtgacttttcttc attcgtcagcaaattgaagggcagaactgtcctggtggtcggggaaaagttgtccgtcccaggc aaaatggttgactggttgtcagaccggcctgaggctaccttcagagctcggctggatttaggca tcccaggtgatgtgcccaaatatgacataatatttgttaatgtgaggaccccatataaatacca tcactatcagcagtgtgaagaccatgccattaagcttagcatgttgaccaagaaagcttgtctg catctgaatcccggcggaacctgtgtcagcataggttatggttacgctgacagggccagcgaaa gcatcattggtgctatagcgcggcagttcaagttttcccgggtatgcaaaccgaaatcctcact tgaagagacggaagttctgtt tgtattcattgggtacgatcgcaaggcccgtacgcacaatcct tacaagctttcatcaaccttgaccaacatttatacaggttccagactccacgaagccggatgtg caccctcatatcatgtggtgcgaggggatattgccacggccaccgaaggagtgattataaatgc tgctaacagcaaaggacaacctggcggaggggtgtgcggagcgctgtataagaaattcccggaa agcttcgatttacagccgatcgaagtaggaaaagcgcgactggtcaaaggtgcagctaaacata tcattcatgccgtaggaccaaacttcaacaaagtttcggaggttgaaggtgacaaacagttggc agaggcttatgagtccatcgctaagattgtcaacgataacaattacaagtcagtagcgattcca ctgttgtccaccggcatcttttccgggaacaaagatcgactaacccaatcattgaaccatttgc tgacagctttagacaccactgatgcagatgtagccatatactgcagggacaagaaatgggaaat gactctcaaggaagcagtggctaggagagaagcagtggaggagatatgcatatccgacgactct tcagtgacagaacctgatgcagagctggtgagggtgcatccgaagagttctttggctggaagga agggctacagcacaagcgatggcaaaactttctcatatttggaagggaccaagtttcaccaggc ggccaaggatatagcagaaattaatgccatgtggcccgttgcaacggaggccaatgagcaggta tgcatgtatatcctcggagaaagcatgagcagtattaggtcgaaatgccccgtcgaagagtcgg aagcctccacaccacctagcacgctgccttgcttgtgcatccatgccatgactccagaaagagt acagcgcctaaaagcctcacgtccagaacaaattactgtgtgctca tcctttccattgccgaag tatagaatcactggtgtgcagaagatccaatgctcccagcctatattgttctcaccgaaagtgc ctgcgtatattcatccaaggaagtatctcgtggaaacaccaccggtagacgagactccggagcc atcggcagagaaccaatccacagaggggacacctgaacaaccaccacttataaccgaggatgag accaggactagaacgcctgagccgatcatcatcgaagaggaagaagaggatagcataagtttgc tgtcagatggcccgacccaccaggtgctgcaagtcgaggcagacattcacgggccgccctctgt atctagctcatcctggtccattcctcatgcatccgactttgatgtggacagtttatccatactt gacaccctggagggagctagcgtgaccagcggggcaacgtcagccgagactaactcttacttcg caaagagtatggagtttctggcgcgaccggtgcctgcgcctcgaacagtattcaggaaccctcc acatcccgctccgcgcacaagaacaccgtcacttgcacccagcagggcctgctcgagaaccagc ctagtttccaccccgccaggcgtgaatagggtgatcactagagaggagctcgaggcgcttaccc cgtcacgcactcctagcaggtcggtctcgagaaccagcctggtctccaacccgccaggcgtaaa tagggtgattacaagagaggagtttgaggcgttcgtagcacaacaacaatgacggtttgatgcg ggtgcatacatcttttcctccgacaccggtcaagggcatttacaacaaaaatcagtaaggcaaa cggtgctatccgaagtggtgttggagaggaccgaattggagatttcgtatgccccgcgcctcga ccaagaaaaagaagaattactacgcaagaaattacagttaaatcccacacctgctaacagaagc agatac cagtccaggaaggtggagaacatgaaagccataacagctagacgtattctgcaaggcc tagggcattatttgaaggcagaaggaaaagtggagtgctaccgaaccctgcatcctgttccttt gtattcatctagtgtgaaccgtgccttttcaagccccaaggtcgcagtggaagcctgtaacgcc atgttgaaagagaactttccgactgtggcttcttactgtattattccagagtacgatgcctatt tggacatggttgacggagcttcatgctgcttagacactgccagtttttgccctgcaaagctgcg cagctttccaaagaaacactcctatttggaacccacaatacgatcggcagtgccttcagcgatc cagaacacgctccagaacgtcctggcagctgccacaaaaagaaattgcaatgtcacgcaaatga gagaattgcccgtattggattcggcggcctttaatgtggaatgcttcaagaaatatgcgtgtaa taatgaatattgggaaacgtttaaagaaaaccccatcaggcttactgaagaaaacgtggtaaat tacattaccaaattaaaaggaccaaaagctgctgctctttttgcgaagacacataatttgaata tgttgcaggacataccaatggacaggtttgtaatggacttaaagagagacgtgaaagtgactcc aggaacaaaacatactgaagaacggcccaaggtacaggtgatccaggctgccgatccgctagca acagcgtatctgtgcggaatccaccgagagctggttaggagattaaatgcggtcctgcttccga acattcatacactgtttgatatgtcggctgaagactttgacgctattatagccgagcacttcca gcctggggattgtgttctggaaactgacatcgcgtcgtttgataaaagtgaggacgacgccatg gctctgaccgcgttaatgattctggaagact taggtgtggacgcagagctgttgacgctgattg aggcggctttcggcgaaatttcatcaatacatttgcccactaaaactaaatttaaattcggagc catgatgaaatctggaatgttcctcacactgtttgtgaacacagtcattaacattgtaatcgca agcagagtgttgagagaacggctaaccggatcaccatgtgcagcattcattggagatgacaata tcgtgaaaggagtcaaatcggacaaattaatggcagacaggtgcgccacctggttgaatatgga agtcaagattatagatgctgtggtgggcgagaaagcgccttatttctgtggagggtttattttg tgtgactccgtgaccggcacagcgtgccgtgtggcagaccccctaaaaaggctgtttaagcttg gcaaacctctggcagcagacgatgaacatgatgatgacaggagaagggcattgcatgaagagtc aacacgctggaaccgagtgggtattctttcagagctgtgcaaggcagtagaatcaaggtatgaa accgtaggaacttccatcatagttatggccatgactactctagctagcagtgttaaatcattca gctacctgagaggggcccctataactctctacggctaacctgaatggactacgacatagtctag tcgagtctagtcgacgccaccatgggcaccgtgaacaagcctgtcgtgggcgtgctgatgggct tcggcatcatcaccggcaccctgagaatcaccaaccctgtgcgggccagcgtgctgagatacga cgacttccacatcgacgaggacaagctggacaccaacagcgtgtacgagccctactaccacagc gaccacgccgagagcagctgggtcaacagaggcgagagcagccggaaggcctacgaccacaaca gcccctacatctggccccggaacgactacgacggcttcctggaaaacgcccacgag caccacgg cgtgtacaatcagggcagaggcatcgacagcggcgagagactgatgcagcccacacagatgagc gcccaggaagatctgggcgacgacacaggcatccacgtgatccccaccctgaacggcgacgacc ggcacaagatcgtgaacgtggaccagcggcagtacggcgacgtgttcaagggcgacctgaaccc taagccccagggccagagactgatcgaggtgtccgtggaagagaaccaccccttcaccctgaga gcccccatccagagaatctacggcgtgcggtataccgagacttggagcttcctgcccagcctga cctgtacaggcgacgccgctcctgccatccagcacatctgcctgaagcacaccacctgtttcca ggacgtggtggtggacgtggactgcgccgagaacaccaaagaggaccagctggccgagatcagc taccggttccagggcaagaaagaggccgaccagccctggatcgtggtcaataccagcaccctgt tcgacgagctggaactggacccccccgagattgaacccggcgtgctgaaggtgctgcggaccga gaagcagtacctgggcgtgtacatctggaacatgcggggctccgacggcacctctacctacgcc accttcctggtcacatggaagggcgacgagaaaacccggaaccctacccctgccgtgacccctc agcctagaggcgccgagttccatatgtggaattaccactcccacgtgttcagcgtgggcgacac cttcagcctggccatgcatctgcagtacaagatccacgaggcccccttcgacctgctgctggaa tggctgtacgtgcccatcgaccctacctgccagcccatgcggctgtacagcacctgtctgtacc accccaacgcccctcagtgcctgagccacatgaacagcggctgcaccttcaccagccctcacct ggctcagagggtggcc agcaccgtgtaccagaattgcgagcacgccgacaactacaccgcctac tgcctgggcatcagccacatggaacccagcttcggcctgatcctgcacgatggcggcaccaccc tgaagttcgtggacacacccgagagcctgagcggcctgtacgtgttcgtggtgtacttcaacgg ccacgtggaagccgtggcctacaccgtggtgtccaccgtggaccacttcgtgaacgccatcgag gaaagaggcttcccacccacagccggacagcctccagccaccaccaagcccaaagaaatcaccc ccgtgaaccccggcaccagccccctgctgagatatgctgcttggacaggcggactggccgctgt ggtgctgctgtgcctggtcatcttcctgatctgcaccgccaagcggatgagagtgaaggcctac cgggtggacaagtccccctacaaccagagcatgtactacgccggcctgcccgtggacgatttcg aggatagcgagagcaccgacaccgaggaagagttcggcaacgccatcggcggatctcacggcgg cagcagctacaccgtgtacatcgacaagaccagataatctagacgtcgcgaccacccaggatcc gcctataactctctacggctaacctgaatggactacgacatagtctagtcgacgccaccatgtt tctgatccagtgcctgatcagcgccgtgatcttctatattcaagtcacaaacgccctgatcttt aagggcgaccacgtgtcactgcaggtcaacagcagcctgaccagcatcctgatccccatgcaga acgacaattacaccgagatcaagggccagctggtgttcatcggcgagcagctgcccaccggcac caattacagcggcaccctggaactgctgtacgccgataccgtggccttctgcttcagaagcgtg caggtcatcagatacgacggctgcccccggatcagaaccag cgccttcatcagctgccggtaca agcacagctggcactacggcaacagcaccgaccggatcagcaccgaacctgatgccggcgtgat gctgaagatcaccaagcccggcatcaacgacgccggcgtgtacgtgctgctcgtgcggctggat cacagcagaagcaccgacggcttcatcctgggcgtgaacgtgtacaccgccggcagccaccaca acatccacggcgtgatctacaccagccccagcctgcagaacggctacagcaccagagccctgtt ccagcaggccagactgtgcgatctgcccgccacacctaagggcagcggcacaagcctgtttcag cacatgctggacctgagagccggcaagagcctggaagataacccctggctgcacgaggacgtgg tcaccaccgagacaaagagcgtggtcaaagagggcatcgagaaccacgtgtaccccaccgacat gagcaccctgcccgagaagtccctgaacgacccccctgagaacctgctgatcatcatccccatc gtggccagcgtgatgatcctgaccgccatggtcatcgtgatcgtgatcagcgtgaagcggcgga gaatcaagaagcaccccatctaccggcccaacaccaagaccagacggggcatccagaacgccac ccctgagtccgacgtgatgctggaagccgccattgcccagctggccaccatcagagaggaaagc ccccctcacagcgtcgtgaaccccttcgtgaagtaatctagacgcggccgcatacagcagcaat tggcaagctgcttacatagaactcgcggcgattggcatgccgccttaaaatttttattttattt ttcttttcttttccgaatcggattttgtttttaatatttcaaaaaaaaaaaaaaaaaaaaaaaa g aaaaaaaaaaagggtcggcatggcatctccacctcctcgcggtccgacctgggcatccgaagga gacgcacgtccactcggatggctaagggagagccacgtttaaaccagctccaattcgccctat agtgagtcgtattacgcgcgctcactggccgtcgttttacaacgtcgtgactgggaaaaccctg gcgttacccaacttaatcgccttgcagcacatccccctttcgccagctggcgtaatagcgaaga ggcccgcaccgatcgcccttcccaacagttgcgcagcctgaatggcgaatgggacgcgccctgt agcggcgcattaagcgcggcgggtgtggtggttacgcgcagcgtgaccgctacacttgccagcg ccctagcgcccgctcctttcgctttcttcccttcctttctcgccacgttcgccggctttccccg tcaagctctaaatcgggggctccctttagggttccgatttagtgctttacggcacctcgacccc aaaaaacttgattagggtgatggttcacgtagtgggccatcgccctgatagacggtttttcgcc ctttgacgttggagtccacgttctttaatagtggactcttgttccaaactggaacaacactcaa ccctatctcggtctattcttttgatttataagggattttgccgatttcggcctattggttaaaa aatgagctgatttaacaaaaatttaacgcgaattttaacaaaatattaacgcttacaatttagg tggcacttttcggggaaatgtgcgcggaacccctatttgtttatttttctaaatacattcaaat atgtatccgctcatgagacaataaccctgataaatgcttcaataatattgaaaaaggaagagta tgagtattcaacatttccgtgtcgcccttattcccttttttgcggcattttgccttcctgtttt tgctcacccagaaacgctggtgaaagtaaaagatgctgaagatcagttgggtgcacgagtgggt tacatcgaactggatctcaacagcgg taagatccttgagagttttcgccccgaagaacgttttc caatgatgagcacttttaaagttctgctatgtggcgcggtattatcccgtattgacgccgggca agagcaactcggtcgccgcatacactattctcagaatgacttggttgagtactcaccagtcaca gaaaagcatcttacggatggcatgacagtaagagaattatgcagtgctgccataaccatgagtg ataacactgcggccaacttacttctgacaacgatcggaggaccgaaggagctaaccgctttttt gcacaacatgggggatcatgtaactcgccttgatcgttgggaaccggagctgaatgaagccata ccaaacgacgagcgtgacaccacgatgcctgtagcaatggcaacaacgttgcgcaaactattaa ctggcgaactacttactctagcttcccggcaacaattaatagactggatggaggcggataaagt tgcaggaccacttctgcgctcggcccttccggctggctggtttattgctgataaatctggagcc ggtgagcgtgggtctcgcggtatcattgcagcactggggccagatggtaagccctcccgtatcg tagttatctacacgacggggagtcaggcaactatggatgaacgaaatagacagatcgctgagat aggtgcctcactgattaagcattggtaactgtcagaccaagtttactcatatatactttagatt gatttaaaacttcatttttaatttaaaaggatctaggtgaagatcctttttgataatctcatga ccaaaatcccttaacgtgagttttcgttccactgagcgtcagaccccgtagaaaagatcaaagg atcttcttgagatcctttttttctgcgcgtaatctgctgcttgcaaacaaaaaaaccaccgcta ccagcggtggtttgtttgccggatcaagagctaccaactctttttccgaag gtaactggcttca gcagagcgcagataccaaatactgttcttctagtgtagccgtagttaggccaccacttcaagaa ctctgtagcaccgcctacatacctcgctctgctaatcctgttaccagtggctgctgccagtggc gataagtcgtgtcttaccgggttggactcaagacgatagttaccggataaggcgcagcggtcgg gctgaacggggggttcgtgcacacagcccagcttggagcgaacgacctacaccgaactgagata cctacagcgtgagctatgagaaagcgccacgcttcccgaagggagaaaggcggacaggtatccg gtaagcggcagggtcggaacaggagagcgcacgagggagcttccagggggaaacgcctggtatc tttatagtcctgtcgggtttcgccacctctgacttgagcgtcgatttttgtgatgctcgtcagg ggggcggagcctatggaaaaacgccagcaacgcggcctttttacggttcctggccttttgctgg ccttttgctcacatgttctttcctgcgttatcccctgattctgtggataaccgtattaccgcct ttgagtgagctgataccgctcgccgcagccgaacgaccgagcgcagcgagtcagtgagcgagga agcggaagagcgcccaatacgcaaaccgcctctccccgcgcgttggccgattcattaatgcagc tggcacgacaggtttcccgactggaaagcgggcagtgagcgcaacgcaattaatgtgagttagc tcactcattaggcaccccaggctttacactttatgctcccggctcgtatgttgtgtggaattgt gagcggataacaatttcacacaggaaacagctatgaccatgattacgccaagcgcgcaattaac 5 VEE-based cctcactaaagggaacaaaagctgggtaccgggcccacgcgtaatacgactcactatag_1377 replicon encoding eGFP nsP1 ~~~~~~~~~~~~~~~~~ 1 ATAGGCGGCG CATGAGAGAA GCCCAGACCA ATTACCTACC CAAAATGGAG AAAGTTCACG nsP1 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 61 CCGCAGTTTG nsP1 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~ 121 AGGTAGAAGC CAAGCAGGTC ACTGATAATG ACCATGCTAA TGCCAGAGCG TTTTCGCATC nsP1 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ "" ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~ 241 GTGCGCCCGC CCGCAGAATG TATTCTAAGC ACAAGTATCA TTGTATCTGT CCGATGAGAT nsP1 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 306 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~ 361 AAATAACTGA TAAGGAATTG GACAAGAAAA TGAAGGAGCT CGCCGCCGTC ATGAGCGACC nsP1 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 421 CTGACCTGGA AACTGAGACT ATGTGCCTCC ACGACGACGA GTCGTGTCGC TACGAAGGGC nsP1 ~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~ 481 AAGTCGCTGT TTACCAGGAT GTATACGCGG TTGACGGACC GACAAGTCTC TATCACCAAG nsP1 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~ 541 CCAATAAGGG AGTTAGAGTC GCCTACTGGA TAGGCTTTGA CACCACCCCT TTTATGTTTA nsP1 ~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 601 AGAACTTGGC TGGAGCATAT CCATCATACT CTACCAACTG GGCCGACGAA ACCGTGTTAA nsP1 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~ 661 CGGCTCGTAA CATAGGCCTA TGCAGCTCTG ACGTTATGGA GCGGTCACGT AGAGGGATGT nsP1 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 721 CCATTCTTAG AAAGAAGTAT TTGAAACCAT CCAACAATGT TCTATTCTCT GTTGGCTCGA nsP1 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~ 781 CCATCTACCA CGAGAAGAGG GACTTACTGA GGAGCTGGCA CCTGCCGTCT GTATTTCACT nsP1 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~ 841 TACGTGGCAA GCAAAATTAC ACATGTCGGT GTGAGACTAT AGTTAGTTGC GACGGGTACG nsP1 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~; ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~ 961 CGATGCACCG CGAGGGATTC TTGTGCTGCA AAGTGACAGA CACATTGAAC GGGGAGAGGG nsP1 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ these are, as we have them in our store at the end of the month! 1021 TCTCTTTTTCC CGTGTGCACG TATGTGCCAG CTACATTGTG TGACCAAATG ACTGGCATAC nsP1 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~ 1081 TGGCAACAGA TGTCAGTGCG GACGACGCGC AAAAACTGCT GGTTGGGCTC AACCAGCGTA nsP1 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 1141 TAGTCGTCAA CGGTCGCACC CAGAGAAACA CCAATACCAT GAAAAATTAC CTTTTGCCCG nsP1 ~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~ 1201 TAGTGGCCCA GGCATTTGCT AGGTGGGCAA AGGAATATAA GGAAGATCAA GAAGATGAAA nsP1 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~ 1261 GGCCACTAGG ACTACGAGAT AGACAGTTAG TCATGGGGTG TTGTTGGGCT TTTAGAAGGC nsP1 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~ 1381 ATTTCCACTC ATTCGTGCTG CCCAGGATAG GCAGTAACAC ATTGGAGATC GGGCTGAGAA nsP1 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ !!! ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 1501 ACGTACAAGA AGCTAAGTGC GCAGCCGATG AGGCTAAGGA GGTGCGTGAA GCCGAGGAGT nsP1 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~! ~~~~~~~~~~~~~~~ nsP1 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ GCTGGGGCCG GCTCAGTGGA GACACCTCGT GGCTTGATAA nsP2 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~ ~~~~~~~~ 1681 AGGTTACCAG CTACGATGGC GAGGACAAGA TCGGCTCTTA CGCTGTGCTT TCTCCGCAGG nsP2 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 1741 CTGTACTCAA GAGTGAAAAA TTATCTTGCA TCCACCCTCT CGCTGAACAA GTCATAGTGA nsP2 ~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~ 1801 TAACACACTC TGGCCGAAAA GGGCGTTATG CCGTGGAACC ATACCATGGT AAAGTAGTGG nsP2 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~ 1861 TGCCAGAGGG ACATGCAATA CCCGTCCAGG ACTTTCAAGC TCTGAGTGAA AGTGCCACCA nsP2 ~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 1921 TTGTGTACAA CGAACGTGAG TTCGTAAACA GGTACCTGCA CCATATTGCC ACACATGGAG nsP2 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~ 1981 GAGCGCTGAA CACTGATGAA GAATATTACA AAACTGTCAA GCCCAGCGAG CACGACGGCG nsP2 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ANN DENTALS GCGTCAAGAA AGAACTAGTC ACTGGGCTAG nsP2 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~ ~~ 2101 GGCTCACAGG CGAGCTGGTG GATCCTCCCT TCCATGAATT CGCCTACGAG AGTCTGAGAA nsP2 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 2121 GCAAGTCTGG CATCATTAAA AGCGCAGTCA CCAAAAAAGA TCTAGTGGTG AGCGCCAAGA nsP2 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~! ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~… ACCCTGTATA nsP2 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~ 2401 TTGACGAAGC TTTTGCTTGT CATGCAGGTA CTCTCAGAGC GCTCATAGCC ATTATAAGAC nsP2 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~... ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~ 252 1 TGAAAGTGCA TTTTAACCAC GAGATTTGCA CACAAGTCTT CCACAAAAGC ATCTCTCGCC nsP2 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ TTGACACTAC CGGCAGTACC AAACCTAAGC nsP2 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~ 2701 AGGACGATCT CATTCTCACT TGTTTCAGAG GGTGGGTGAA GCAGTTGCAA ATAGATTACA nsP2 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 2761 AAGGCAACGA AATAATGACG GCAGCTGCCT CTCAAGGGCT GACCCGTAAA GGTGTGTATG nsP2 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~ 2821 CCGTTCGGTA CAAGGTGAAT GAAAATCCTC TGTACGCACC CACCTCAGAA CATGTGAACG nsP2 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ !!! ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~ 2941 TAAA AACACT GACTGCCAAG TACCCTGGGA ATTTCACTGC CACGATAGAG GAGTGGCAAG nsP2 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~... GGTGCTGAAG ACCGCTGGCA nsP2 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~ 3121 TAGACATGAC CACTGAACAA TGGAACACTG TGGATTATTT TGAAACGGAC AAAGCTCACT nsP2 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 3181 CAGCAGAGAT AGTATTGAAC CAACTATGCG TGAGGTTCTT TGGACTCGAT CTGGACTCCG nsP2 ~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~ 3241 GTCTATTTTC TGCACCCACT GTTCCGTTAT CCATTAGGAA TAATCACTGG GATAACTCCC nsP2 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 3301 CGTCGCCTAA CATGTACGGG CTGAATAAAG AAGTGGTCCG TCAGCTCTCT CGCAGGTACC nsP2 ~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~ 3361 CACAACTGCC TCGGGCAGTT GCCACTGGAA GAGTCTATGA CATGAACACT GGTACACTGC nsP2 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~ 3421 GCAATTATGA TCCGCGCATA AACCTAGTAC CTGTAAACAG AAGACTGCCT CATGCTTTAG nsP2 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ' AAATTGAAGG nsP2 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~ 3541 GCAGAACTGT CCTGGTGGTC GGGGAAAAGT TGTCCGTCCC AGGCAAAATG GTTGACTGGT nsP2 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 3601 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~ 3661 TGCCCAAATA TGACATAATA TTTGTTAATG TGAGGACCCC ATATAAATAC CATCACTATC nsP2 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 3721 AGCAGTGTGA AGACCATGCC ATTAAGCTTA GCATGTTGAC CAAGAAAGCT TGTCTGCATC nsP2 ~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~ 3781 TGAATCCCGG CGGAA CCTGT GTCAGCATAG GTTATGGTTA CGCTGACAGG GCCAGCGAAA nsP2 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~ 3841 GCATCATTGG TGCTATAGCG CGGCAGTTCA AGTTTTCCCG GGTATGCAAA CCGAAATCCT nsP2 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 3901 CACTTGAAGA GACGGAAGTT CTGTTTGTAT TCATTGGGTA CGATCGCAAG GCCCGTACGC nsP2 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~ 3961 ACAATCCTTA CAAGCTTTCA TCAACCTTGA CCAACATTTA TACAGGTTCC AGACTCCACG nsP3 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~ nsP2 ~~~~~~~~~~~~ 4021 AAGCCGGATG TGCACCCTCA TATCATGTGG TGCGAGGGGA TATTGCCACG GCCACCGAAG nsP3 ~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~ 4081 GAGTGATTAT AAATGCTGCT AACAGCAAAG GACAACCTGG CGGAGGGGTG TGCGGAGCGC nsP3 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 4141 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~ 4201 TGGTCAAAGG TGCAG CTAAA CATATCATTC ATGCCGTAGG ACCAAACTTC AACAAAGTTT nsP3 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~ 4261 CGGAGGTTGA AGGTGACAAA CAGTTGGCAG AGGCTTATGA GTCCATCGCT AAGATTGTCA nsP3 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 2121 TTTTCCGGGA nsP3 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~ 4381 ACAAAGATCG ACTAACCCAA TCATTGAACC ATTTGCTGAC AGCTTTAGAC ACCACTGATG nsP3 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 4441 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~ 4501 CTAGGAGAGA AGCAGTGGAG GAGATATGCA TATCCGACGA CTCTTCAGTG ACAGAACCTG nsP3 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 4561 ATGCAGAGCT GGTGAGGGTG CATCCGAAGA GTTCTTTGGC TGGAAGGAAG GGCTACAGCA nsP3 ~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~ 4621 CAAGCGATGG CAAAACTTTC TCATATTTGG AAGGGACCAA GTTTCACCAG GCGGCCAAGG nsP3 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~ 4681 ATATAGCAGA AATTAATGCC ATGTGGCCCG TTGCAACGGA GGCCAATGAG CAGGTATGCA nsP3 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 4741 TGTATATCCT CGGAGAAAGC ATGAGCAGTA TTAGGTCGAA ATGCCCCGTC GAAGAGTCGG nsP3 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~ 4801 AAGCCTCCAC ACCACCTAGC ACGCTGCCTT GCTTGTGCAT CCATGCCATG ACTCCAGAAA nsP3 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ !! ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~ 4921 TGCCGAAGTA TAGAATCACT GGTGTGCAGA AGATCCAATG CTCCCAGCCT ATATTGTTCT nsP3 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 4981 CACCGAAAGT GCCTGCGTAT ATTCATCCAA GGAAGTATCT CGTGGAAACA CCACCGGTAG nsP3 ~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~ 5041 ACGAGACTCC GGAGCCATCG GCAGAG AACC AATCCACAGA GGGGACACCT GAACAACCAC nsP3 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ " nsP3 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~ 5221 AGGCAGACAT TCACGGGCCG CCCTCTGTAT CTAGCTCATC CTGGTCCATT CCTCATGCAT nsP3 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 5281 CCGACTTTGA TGTGGACAGT TTATCCATAC TTGACACCCT GGAGGGAGCT AGCGTGACCA nsP3 ~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~ 5341 GCGGGGCAAC GTCAGCCGAG ACTAACTCTT ACTTCGCAAA GAGTATGGAG TTTCTGGCGC nsP3 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 5401 GACCGGTGCC TGCGCCTCGA ACAGTATTCA GGAACCCTCC ACATCCCGCT CCGCGCACAA nsP3 ~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~ 5461 GAACACCGTC ACTTGCACCC AGCAGGGCCT G CTCGAGAAC CAGCCTAGTT TCCACCCCGC nsP3 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~ 5521 CAGGCGTGAA TAGGGTGATC ACTAGAGAGG AGCTCGAGGC GCTTACCCCG TCACGCACTC nsP3 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ " ~~~~~~~~~~~~~~~~~~~ nsP3 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~ 5641 TTACAAGAGA GGAGTTTGG GCGTTCGTAG CACAACAACA ATGACGGTTT GATGCGGGTG nsP4 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 5701 CATACATCTT TTCCTCCGAC ACCGGTCAAG GGCATTTACA ACAAAAATCA GTAAGGCAAA nsP4 ~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~ 5761 CGGTGCTATC CGAAGTGGTG TTGGAGAGGA CCGAATTGGA GATTTCGTAT GCCCCGCGCC nsP4 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 5821 TCGACCAAGA AAAAGAAGAA TTACTACGCA AGAAATTACA GTTAAATCCC ACACCTGCTA nsP4 ~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~ 5881 ACAGAAGCAG ATACCAGTCC AGGAAGGTGG A GAACATGAA AGCCATAACA GCTAGACGTA nsP4 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~ 5941 TTCTGCAAGG CCTAGGGCAT TATTTGAAGG CAGAAGGAAA AGTGGAGTGC TACCGAACCC nsP4 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 6001 TGCATCCTGT TCCTTTGTAT TCATCTAGTG TGAACCGTGC CTTTTCAAGC CCCAAGGTCG nsP4 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~ 6061 CAGTGGAAGC CTGTAACGCC ATGTTGAAAG AGAACTTTCC GACTGTGGCT TCTTACTGTA nsP4 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 6121 TTATTCCAGA GTACGATGCC TATTTGGACA TGGTTGACGG AGCTTCATGC TGCTTAGACA nsP4 ~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~ 6181 CTGCCAGTTT TTGCCCTGCA AAGCTGCGCA GCTTTCCAAA GAAACACTCC TATTTGGAAC nsP4 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ... ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~ 6301 CTGCCACAAA AAGAAATTGC AATGTCACGC AAATGAG AGA ATTGCCCGTA TTGGATTCGG nsP4 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~ 6361 CGGCCTTTAA TGTGGAATGC TTCAAGAAAT ATGCGTGTAA TAATGAATAT TGGGAAACGT nsP4 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ... ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~ 6481 AAGGACCAAA AGCTGCTGCT CTTTTTGCGA AGACACATAA TTTGAATATG TTGCAGGACA nsP4 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~… ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~ 6601 AACATACTGA AGAACGGCCC AAGGTACAGG TGATCCAGGC TGCCGATCCG CTAGCAACAG nsP4 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 6661 CGTATCTGTG CGGAATCCAC CGAGAGCTGG TTAGGAGATT AAATGCGGTC CTGCTTCCGA nsP4 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ " ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~ 6721 ACATTCATAC ACTGTTTGAT ATGTCGGCTG AAGACTTTGA CG CTATTATA GCCGAGCACT nsP4 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~ 6781 TCCAGCCTGG GGATTGTGTT CTGGAAACTG ACATCGCGTC GTTTGATAAA AGTGAGGACG nsP4 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ” ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~ 6901 TGACGCTGAT TGAGGCGGCT TTCGGCGAAA TTTCATCAAT ACATTTGCCC ACTAAAACTA nsP4 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 6 A61 ALL AATTTAAATT ThisGGGCCCCATG ATGAAATCTG GAATGTTCCT CACACTGTTT GTGAACACAG nsP4 ~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~ 7021 TCATTAACAT TGTAATCGCA AGCAGAGTGT TGAGAGAACG GCTAACCGGA TCACCATGTG nsP4 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ performed818181 by 81 708181818181818181818181 7081 CAGCATTCAT TGGAGATGAC AATATCGTGA AAGGAGTCAA ATCGGACAAA TTAATGGCAG by nsP4 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~ 7141 ACAGGTGCGC CACCTGGTTG AATATGGAAG TCAAGATTAT AGATGCTG TG GTGGGCGAGA nsP4 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 7261 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~ 7321 AACATGATGA TGACAGGAGA AGGGCATTGC ATGAAGAGTC AACACGCTGG AACCGAGTGG nsP4 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~quey'uway on ayyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyy ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~ 7441 TCATAGTTAT GGCCATGACT ACTCTAGCTA GCAGTGTTAA ATCATTCAGC TACCTGAGAG subgenomic promoter ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~ 7501 GGGCCCCTAT AACTCTCTAC GGCTAACCTG AATGGACTAC GACATAGTCT AGTCGACGCC eGFP ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ !! CCT GGTCGAGCTG eGFP ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~ 7621 GACGGCGACG TAAACGGCCA CAAGTTCAGC GTGTCCGGCG AGGGCGAGGG CGATGCCACC eGFP ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 7681 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~ 7741 ACCCTCGTGA CCACCCTGAC CTACGGCGTG CAGTGCTTCA GCCGCTACCC CGACCACATG eGFP ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 7801 AAGCAGCACG ACTTCTTCAA GTCCGCCATG CCCGAAGGCT ACGTCCAGGA GCGCACCATC eGFP ~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~ 7861 TTCTTCAAGG ACGACGGCAA CTACAAGACC CGCGCCGAGG TGAAGTTCGA GGGCGACACC eGFP ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~ 7981 CACAAGCTGG AGTACAACTA CAACAGCCAC AACGTCTATA TCATGGCCGA CA AGCAGAAG eGFP ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~ 8041 AACGGCATCA AGGTGAACTT CAAGATCCGC CACAACATCG AGGACGGCAG CGTGCAGCTC eGFP ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 8101 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~ 8161 CACTACCTGA GCACCCAGTC CGCCCTGAGC AAAGACCCCA ACGAGAAGCG CGATCACATG eGFP ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ "" ~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~ 8341 TACATAGAAC TCGCGGCGAT TGGCATGCCG CCTTAAAATT TTTATTTTAT TTTTCTTTTC 3'UTR ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 8401 TTTTCCGAAT CGGATTTTGG TTTTAATATT TCAAAAAAAA AAAAAAAAAA AAAAAAAAAA HDA ribozyme ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~ 8461 AAAAAAAGGG TCGGCATGGC ATCTCCACCT CCTCGCGGTC CGACCTGGGC ATCCGAAGGA HDV ribozyme ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~ 8521 GGACGCACGT CCACTCGGAT GGCTAAGGGA GAGCCACGTT TAAACCAGCT CCAATTCGCC 8581 CTATAGTGAG TCGTATTACG CGCGCTCACT GGCCGTCGTT TTACAACGTC GTGACTGGGA 8641 AAACCCTGGC GTTACCCAAC TTAATCGCCT TGCAGCACAT CCCCCTTTCG CCAGCTGGCG 8701 TAATAGCGAA GAGGCCCGCA CCGATCGCCC TTCCCAACAG TTGCGCAGCC TGAATGGCGA 8761 ATGGGACGCG CCCTGTAGCG GCGCATTAAG CGCGGCGGGT GTGGTGGTTA CGCGCAGCGT 8821 GACCGCTACA CTTGCCAGCG CCCTAGCGCC CGCTCCTTTC GCTTTCTTCC CTTCCTTTCT 8881 CGCCACGTTC GCCGGCTTTC CCCGTCAAGC TCTAAATCGG GGGCTCCCTT TAGGGTTCCG 8941 ATTTAGTGCT TTACGGCACC TCGACCCCAA AAAACTTGAT TAGGGTGATG GTTCACGTAG 9001 TGGGCCATCG CCCTGATAGA CGGTTTTTCG CCCTTTGACG TTGGAGTCCA CGTTCTTTAA 9061 TAGTGGACTC TTGTTCCAAA CTGGAACAAC ACTCAACCCT ATCTCGGTCT ATTCTTTTGA 9121 TTTATAAGGG ATTTTGCCGA TTTCGGCCTA TTGGTTAAAA AATGAGCTGA TTTAACAAAA 9181 ATTTAACGCG AATTTTAACA AAATATTAAC GCTTACAATT TAGGTGGCAC TTTTCGGGGA 9 241 AATGTGCGCG GAACCCCTAT TTGTTTATTT TTCTAAATAC ATTCAAATAT GTATCCGCTC bla ~~~~~~~~~ 9301 ATGAGACAAT AACCCTGATA AATGCTTCAA TAATATTGAA AAAGGAAGAG TATGAGTATT t ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ *** *** AL *** UP ON E WHAT EVER ... 9361 CAACATTTCC GTGTCGCCCT TATTCCCTTT TTTGCGGCAT TTTGCCTTCC TGTTTTTGCT bla ~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~ 9421 CACCCAGAAA CGCTGGTGAA AGTAAAAGAT GCTGAAGATC AGTTGGGTGC ACGAGTGGGT bla ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Sorrykekei ... ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~ 9541 TTTCCAATGA TGAGCACTTT TAAAGTTCTG CTATGTGGCG CGGTATTATC CCGTATTGAC bla ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~# ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~ 9661 TCACCAGTCA CAGAAAAGCA TCTTACGGAT GGCATGACAG TAAGAGAATT ATGCAGTGCT bla ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~ 9721 GCCATAACCA TGAGTGATAA CACTGCGGCC AACTTACTTC TGACAACGAT CGGAGGACCG bla ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 9781 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~ 9841 GAACCGGAGC TGAATGAAGC CATACCAAAC GACGAGCGTG ACACCACGAT GCCTGTAGCA bla ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 9901 ATGGCAACAA CGTTGCGCAA ACTATTAACT GGCGAACTAC TTACTCTAGC TTCCCGGCAA bla ~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~ 9961 CAATTAATAG ACTGGATGGA GGCGGATAAA GTTGCAGGAC CACTTCTGCG CTCGGCCCTT bla ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 10021 CCGGCTGGCT GGTTTATTGC TGATAAATCT GGAGCCGGTG AGCGTGGGTC TCGCGGTATC bla ~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~ 10081 ATTGCAGCAC TGGGGCCAGA TGGTAAGCCC TCCCGTATCG TAGTTATCTA CACGACGGGG bla ~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~ 10141 AGTCAGGCAA CTATGGATGA ACGAAATAGA CAGATCGCTG AGATAGGTGC CTCACTGATT bla ~~~~~~~~~ 10201 AAGCATTGGT AACTGTCAGA CCAAGTTTAC TCATATATAC TTTAGATTGA TTTAAAACTT 10261 CATTTTTAAT TTAAAAGGAT CTAGGTGAAG ATCCTTTTTG ATAATCTCAT GACCAAAATC 10321 CCTTAACGTG AGTTTTCGTT CCACTGAGCG TCAGACCCCG TAGAAAAGAT CAAAGGATCT 10381 TCTTGAGATC CTTTTTTTCT GCGCGTAATC TGCTGCTTGC AAACAAAAAA ACCACCGCTA 10441 CCAGCGGTGG TTTGTTTGCC GGATCAAGAG CTACCAACTC TTTTTCCGAA GGTAACTGGC 10501 TTCAGCAGAG CGCAGATACC AAATACTGTT CTTCTAGTGT AGCCGTAGTT AGGCCACCAC 10561 TTCAAGAACT CTGTAGCACC GCCTACATAC CTCGCTCTGC TAATCCTGTT ACCAGTGGCT 10621 GCTGCCAGTG GCGATAAGTC GTGTCTTACC GGGTTGGACT CAAGACGATA GTTACCGGAT 10681 AAGGCGCAGC GGTCGGGCTG AACGGGGGGT TCGTGCACAC AGCCCAGCTT GGAGCGAACG 10741 ACCTACACCG AACTGAGATA CCTACAGCGT GAGCTATGAG AAAGCGCCAC GCTTCCCGAA 10801 GGGAGAAAGG CGGACAGGTA TCCGGTAAGC GGCAGGGTCG GAACAGGAGA GCGCACGAGG 10861 GAGCTTCCAG GGGGAAACGC CTGGTATCTT TATAGTCCTG TCGGGTTTCG C CACCTCTGA 10921 CTTGAGCGTC GATTTTTGTG ATGCTCGTCA GGGGGGCGGA GCCTATGGAA AAACGCCAGC 10981 AACGCGGCCT TTTTACGGTT CCTGGCCTTT TGCTGGCCTT TTGCTCACAT GTTCTTTCCT 11041 GCGTTATCCC CTGATTCTGT GGATAACCGT ATTACCGCCT TTGAGTGAGC TGATACCGCT 11101 CGCCGCAGCC GAACGACCGA GCGCAGCGAG TCAGTGAGCG AGGAAGCGGA AGAGCGCCCA 11161 ATACGCAAAC CGCCTCTCCC CGCGCGTTGG CCGATTCATT AATGCAGCTG GCACGACAGG 11221 TTTCCCGACT GGAAAGCGGG CAGTGAGCGC AACGCAATTA ATGTGAGTTA GCTCACTCAT 11281 TAGGCACCCC AGGCTTTACA CTTTATGCTC CCGGCTCGTA TGTTGTGTGG AATTGTGAGC 11341 GGATAACAAT TTCACACAGG AAACAGCTAT GACCATGATT ACGCCAAGCG CGCAATTAAC 11401 CCTCACTAAA GGGAACAAAA GCTGGGTACC GGGCCCACGC GTAATACGAC TCACTATAG VEE cap helper 5'UTR ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~! ~~~~~~~~~~~~~~~~~~ nsP1 ~~~~~~~~~~~~~~~~~ 1 ATAGGCGGCG CATGAGAGAA GCCCAGACCA ATTACCTACC CAAATAGGAG AAAGTTCACG nsP1 ~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~ 61 TTGACATCGA GGAAGACAGC CCATTCCTCA GAGCTTTGCA GCGGAGCTTC CCGCAGTTTG nsP1 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 121 AGGTAGAAGC CAAGCAGGTC ACTGATAATG ACCATGCTAA TGCCAGAGCG TTTTCGCATC nsP1 ~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 181 TGGCTTCAAA ACTGATCGAA ACGGAGGTGG ACCCATCCGA CACGATCCTT GACATTGGAC VEECAP ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~ 241 GGACCGACCA TGTTCCCGTT CCAGCCAATG TATCCGATGC AGCCAATGCC CTATCGCAAC VEECAP ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ GDDDDDDDDDDDDD at WHAT TO GET TO GET AVAILABLE ECCTECECECECEC~CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCGGGCCCCCCG CCCC ACGGGGGGCCGGGCCGGCCGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGG ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~ 361 GTGCAGGAAT TAACCCGCTC GATGGCTAAC CTGACGTTCA AGCAACGCCG GGACGCGCCA VEECAP ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 421 CCTGAGGGGC CATCCGCTAA GAAACCGAAG AAGGAGGCCT CGCAAAAACA GAAAGGGGGA VEECAP ~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~ 481 GGCCAAGGGA AGAAGAAGAA GAACCAAGGG AAGAAGAAGG CTAAGACAGG GCCGCCTAAT VEECAP ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~ 541 CCGAAGGCAC AGAATGGAAA CAAGAAGAAG ACCAACAAGA AACCAGGCAA GAGACAGCGC VEECAP ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~ H152G ~~~ 661 GGCTACGCTT GTGTGGTCGG AGGGAAGTTA TTCAGGCCGA TGGGTGTGGA AGGCAAGATC VEECAP ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ G GD G D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D Dav aren't following this property: 721 GACAACGACG TTCTGGCCGC GCTTAAGACG AAGAAAGCAT CCAAATACGA TCTTGAGTAT VEECAP ~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~ 781 GCAGATGTGC CACAGAACAT GCGGGCCGAT ACATTCAAAT ACACCCATGA GAAACCCCAA VEECAP ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 841 GGCTATTACA GCTGGCATCA TGGAGCAGTC CAATATGAAA ATGGGCGTTT CACGGTGCCG VEECAP ~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~ 901 AAAGGAGTTG GGGCCAAGGG AGACAGCGGA CGACCCATTC TGGATAACCA GGGACGGGTG VEECAP ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ !!! ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~ 1021 TGGAACGAGA AGGGAGTTAC CGTGAAGTAT ACTCCGGAGA ACTGCGAGCA ATGGTAATAG VEECAP 3'UTR ~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~ 1081 TAAGCGGCCG CATACAGCAG CAATTGGCAA GCTGCTTACA TAGAACTCGC GGCGATTGGC 3'UTR ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 1141 ATGCCGCCTT AAAATTTTTA TTTTATTTTTT CTTTTCTTTT CCGAATCGGA TTTTGTTTTTTTT 3'UTR HDV ribozyme ~~~~~~~~ ~~~~~~~~~~~~~~~~~~ 1201 AATATTTCAA AAAAAAAAAA AAAAAAAAA AAAAAAAAAA AAAGGGTCGG CATGGCATCT HDV ribozyme ~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~ 1261 CCACCTCCTC GCGGTCCGAC CTGGGCATCC GAAGGAGGAC GCACGTCCAC TCGGATGGCT HDV ribozyme ~~~~~~~~~~~~~~ 1321 AAGGGAGAGC CACGTTTAAA CACGTGATAT CTGGCCTCAT GGGCCTTCCT TTCACTGCCC 1381 GCTTTCCAGT CGGGAAACCT GTCGTGCCAG CTGCATTAAC ATGGTCATAG CTGTTTCCTT 1441 GCGTATTGGG CGCTCTCCGC TTCCTCG CTC ACTGACTCGC TGCGCTCGGT CGTTCGGGTA colE1 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~ 1501 AAGCCTGGGG TGCCTAATGA GCAAAAGGCC AGCAAAAGGC CAGGAACCGT AAAAAGGCCG colE1 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ all everything ... all ... all ...... ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Dddd ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 2121 GTGGCGAAAC CCGACAGGAC TATAAAGATA CCAGGCGTTTPCCTCTGGAA colE1 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~ 1681 GCTCCCTCGT GCGCTCTCCT GTTCCGACCC TGCCGCTTAC CGGATACCTG TCCGCCTTTC colE1 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 1741 TCCCTTCGGG AAGCGTGGCG CTTTCTCATA GCTCACGCTG TAGGTATCTC AGTTCGGTGT colE1 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~ 1801 AGGTCGTTCG CTCCAAGCTG GGCTGTGTGC ACGAACCCCC CGTTCAGCCC GACCGCTGCG colE1 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 1861 CCTTATCCGG TAACTATCGT CTTGAGTCCA ACCCGGTAAG AC ACGACTTA TCGCCACTGG colE1 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ TGAAGTGGTG GCCTAACTAC GGCTACACTA GAAGAACAGT ATTTGGTATC TGCGCTCTGC colE1 ~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~ 2041 TGAAGCCAGT TACCTTCGGA AAAAGAGTTG GTAGCTCTTG ATCCGGCAAA CAAACCACCG colE1 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 2101 CTGGTAGCGG TGGTTTTTTTT GTTTGCAAGC AGCAGATTAC GCGCAGAAAA AAAGGATCTC cole1 ~~~~~ ~~~~~~~~~~~~~~~~~~~~~~ 2161 AAGAAGATCC TTTGATCTTT TCTACGGGGT CTGACGCTCA GTGGAACGAA AACTCACGTT 2221 AAGGGATTTT GGTCATGAGA TTATCAAAAA GGATCTTCAC CTAGATCCTT TTAAATTAAA 2281 AATGAAGTTT TAAATCAATC TAAAGTATAT ATGAGTAAAC TTGGTCTGAC AGTTATTAGA Kan ~~~ 2341 AAAATTCATC CAGCAGACGA TAAAACGCAA TACGCTGGCT ATCCGGTGCC GCAATGCCAT ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~ KanR 2401 ACAGC ACCAG AAAACGATCC GCCCATTCGC CGCCCAGTTC TTCCGCAATA TCACGGGTGG ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~ KanR 2461 CCAGCGCAAT ATCCTGATAA CGATCCGCCA CGCCCAGACG GCCGCAATCA ATAAAGCCGC ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ KanR 2521 TAAAACGGCC ATTTTCCACC ATAATGTTCG GCAGGCACGC ATCACCATGG GTCACCACCA ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~ KanR 2581 GATCTTCGCC ATCCGGCATG CTCGCTTTCA GACGCGCAAA CAGCTCTGCC GGTGCCAGGC ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ KanR 2641 CCTGATGTTC TTCATCCAGA TCATCCTGAT CCACCAGGCC CGCTTCCATA CGGGTACGCG ~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~ KanR 2701 CACGTTCAAT ACGATGTTTC GCCTGATGAT CAAACGGACA GGTCGCCGGG TCCAGGGTAT ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ KanR 2761 GCAGACGACG CATGGCATCC GCCATAATGC TCACTTTTTC TGCCGGCGCC AGATGGCTAG ~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~ KanR 2821 ACAGCAGATC CTGACCCGGC ACTTCGCCCA GCAGCAGCCA ATCACGGCCC GCTTCGGTCA ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~ KanR 2881 CCACATCCAG CACCGCCGCA CACGGAACAC CGGTGGTGGC CAGCCAGCTC AGACGCGCCG ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ KanR 2941 CTTCATCCTG CAGCTCGTTC AGCGCACCGC TCAGATCGGT TTTCACAAAC AGCACCGGAC ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~ KanR 3001 GACCCTGCGC GCTCAGACGA AACACCGCCG CATCAGAGCA GCCAATGGTC TGCTGCGCCC ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~! ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~ Kan R 3121 GTTCAATCAT ACTCTTCCTT TTTCAATATT ATTGAAGCAT TTATCAGGGT TATTGTCTCA ~~~~~~~~~~~ Kan R 3181 TGAGCGGATA CATATTTGAA TGTATTTAGA AAAATAAACA AATAGGGGTT CCGCGCACAT 3241 TTCCCCGAAA AGTGCCACCT AAATTGTAAG CGTTAATATT TTGTTAAAAT TCGCGTTAAA 3301 TTTTTGTTAA ATCAGCTCAT TTTTTAACCA ATAGGCCGAA ATCGGCAAAA TCCCTTATAA 3361 ATCAAAAGAA TAGACCGAGA TAGGGTTGAG TGGCCGCTAC AGGGCGCTCC CATTCGCCAT 3421 TCAGGCTGCG CAACTGTTGG GAAGGGCGTT TCGGTGCGGG CCTCTTCGCT ATTACGCCAG 3481 CTGGCGAAAG GGGGATGTGC TGCAAGGCGA TTAAGTTGGG TAACGCCAGG GTTTTCCCAG T7 promoter ~~~~~~~~~~~~~~~~~~~~ 3541 TCACACGCGT AATACGACTC ACTATAG VEE helper gly 5 'UTR ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ nsP1 ~~~~~~~~~~~~~~~~~ 1 ATAGGCGGCG CATGAGAGAA GCCCAGACCA ATTACCTACC CAAATAGGAG AAAGTTCACG nsP1 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ " ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~ 121 AGGTAGAAGC CAAGCAGGTC ACTGATAATG ACCATGCTAA TGCCAGAGCG TTTTCGCATC nsP1 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 181 TGGCTTCAAA ACTGATCGAA ACGGAGGTGG ACCCATCCGA CACGATCCTT GACATTGGAC VEE GLY ~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~ 241 GGACCGACCA TGTCACTAGT GACCACCATG TGTCTGCTCG CCAATGTGAC GTTCCCATGT VEE GLY ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~ 301 GCTCAACCAC CAATTTGCTA CGACAGAAAA CCAGCAGAGA CTTTGGCCAT GCTCAGCGTT VEE GLY ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~ 421 AAAAGGAGAT CCACCGAGGA GCTGTTTAAT GAGTATAAGC TAACGCGCCC TTACATGGCC VEE GLY ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~ 541 AGCGACGGGC ACGACGGTTA TGTTAGACTT CAGACTTCCT CGCAGTATGG CCTGGATTCC VEE GLY ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 601 TCCGGCAACT TAAAGGGCAG GACCATGCGG TATGACATGC ACGGGACCAT TAAAGAGATA VEE GLY ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~ 661 CCACTACATC AAGTGTCACT CTATACATCT CGCCCGTGTC ACATTGTGGA TGGGCACGGT VEE GLY ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~ 721 TATTTCCTGC TTGCCAGGTG CCCGGCAGGG GACTCCATCA CCATGGAATT TAAGAAAGAT VEE GLY ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 7 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~ 841 CTCTATACTC ATCCCCCAGA ACACGGAGTA GAGCAAGCGT GCCAAGTCTA CGCACATGAT VEE GLY ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~ 961 TTGGTTTCCT TGAGCGGCAG TTCAGTCACC GTGACACCTC CTGATGGGAC TAGCGCCCTG VEE GLY ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 1021 GTGGAATGCG AGTGTGGCGG CACAAAGATC TCCGAGACCA TCAACAAGAC AAAACAGTTC VEE GLY ~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~ 1081 AGCCAGTGCA CAAAGAAGGA GCAGTGCAGA GCATATCGGC TGCAGAACGA TAAGTGGGTG VEE GLY ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~ 1141 TATAATTCTG ACAAACTGCC CAAAGCAGCG GGAGCCACCT TAAAAGGAAA ACTGCATGTC VEE GLY ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 1201 CCATTCTTGG TGGCAGACGG CAAATGCACC GTGCCTCTAG CACCAGAACC TATGATAACC VEE GLY ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~ 1261 TTCGGTTTCA GATCAGTGTC ACTGAAACTG CACCCTAAGA ATCCCACATA TCTAATCACC VEE GLY ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 1321 CGCCAACTTG CTGATGAGCC TCACTACACG CACGAGCTCA TATCTGAACC AGCTGTTAGG VEE GLY ~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ” ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~ 1501 CATTATTACC ACAGATACCC TATGTCCACC ATCCTGG GTT TGTCAATTTG TGCCGCCATT VEE GLY ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~... GCTTTGCTGC VEE GLY ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~ 1681 GCCCGCACTG CCCGGGCCGA GACCACCTGG GAGTCCTTGG ATCACCTATG GAACAATAAC VEE GLY ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Service use life time to view, view, download, and review any photos on our site. 1741 CAACAGATGT TCTGGATTCA ATTGCTGATC CCTCTGGCCG CCTTGATCGT AGTGACTCGC VEE GLY ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~ 1801 CTGCTCAGGT GCGTGTGCTG TGTCGTGCCT TTTTTAGTCA TGGCCGGCGC CGCAGGCGCC VEE GLY ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 1861 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~ 1921 GTCAACAGAG CAGGCTACGC ACC ACTCCCT ATCAGCATAA CACCAACAAA GATCAAGCTG VEE GLY ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~ 1981 ATACCTACAG TGAACTTGGA GTACGTCACC TGCCACTACA AAACAGGAAT GGATTCACCA VEE GLY ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 2041 GCCATCAAAT GCTGCGGATC TCAGGAATGC ACTCCAACTT ACAGGCCTGA TGAACAGTGC VEE GLY ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~ 2101 AAAGTCTTCA CAGGGGTTTA CCCGTTCATG TGGGGTGGTG CATATTGCTT TTGCGACACT VEE GLY ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 2161 GAGAACACCC AAGTCAGCAA GGCCTACGTA ATGAAATCTG ACGACTGCCT TGCGGATCAT VEE GLY ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~ 2221 GCTGAAGCAT ATAAAGCGCA CACAGCCTCA GTGCAGGCGT TCCTCAACAT CACAGTGGGA VEE GLY ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ' ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~ 2341 GTCAAAATAA CTGCAGGTCC GCTTTCCACA GCTTGGACAC CCTTTGATCG CAAAATCGTG VEE GLY ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~ 2401 CAGTATGCCG GGGAGATCTA TAATTATGAT TTTCCTGAGT ATGGGGCAGG ACAACCAGGA VEE GLY ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 2461 GCATTTGGAG ATATACAATC CAGAACAGTC TCAAGCTCTG ATCTGTATGC CAATACCAAC VEE GLY ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~ 2521 CTAGTGCTGC AGAGACCCAA AGCAGGAGCG ATCCACGTGC CATACACTCA GGCACCTTCG VEE GLY ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ... CCCTTTCGGA VEE GLY ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~ 2641 TGCGAAATAT ATACAAACCC CATTCGCGCC GAAAACTGTG CTGTAGGGTC AATTCCATTA VEE GLY ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ !!! " GLY ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~ 2761 GCCGAATGCA CTCTTAACGA GTGCGTGTAT TCTTCCGACT TTGGTGGGAT CGCCACGGTC VEE GLY ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~ 2821 AAGTACTCGG CCAGCAAGTC AGGCAAGTGC GCAGTCCATG TGCCATCAGG GACTGCTACC VEE GLY ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ CAGCAGTCGA GCTAACCGAG CAAGGGTCGG CGACTATCCA TTTCTCGACC VEE GLY ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~ 2941 GCAAATATCC ACCCGGAGTT CAGGCTCCAA ATATGCACAT CATATGTTAC GTGCAAAGGT VEE GLY ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 1 ACACACCCTC AGTATCACGC CCAAACATTT VEE GLY ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~ 3061 ACAGCCGCGG TGTCAAAAAC CGCGTGGACG TGGTTAACAT CCCTGCTGGG AGGATCAGCC VEE GLY ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 3121 GTAATTATTA TAATTGGCTT GGTGCTGGCT ACTATTGTGG CCATGTACGT GCTGACCAAC VEE GLY 3'UTR ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~ 3181 CAGAAACATA ATTAATAGTA AGCGGCCGCA TACAGCAGCA ATTGGCAAGC TGCTTACATA 3'UTR ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~61 AGGGTCGGCA TGGCATCTCC ACCTCCTCGC GGTCCGACCT GGGCATCCGA AGGAGGACGC HDV ribozyme ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 3421 ACGTCCACTC GGGGGGA GCCTTCCTTT CACTGCCCGC TTTCCAGTCG GGAAACCTGT CGTGCCAGCT GCATTAACAT 3541 GGTCATAGCT GTTTCCTTGC GTATTGGGCG CTCTCCGCTT CCTCGCTCAC TGACTCGCTG colE1 ~~~~~~~~~~~~~~~~~~~~~~~~~~~ 3601 CGCTCGGTCG TTCGGGTAAA GCCTGGGGTG CCTAATGAGC AAAAGGCCAG colE1 ~ CAAAAGGCCA ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~ 3661 GGAACCGTAA AAAGGCCGCG TTGCTGGCGT TTTTCCATAG GCTCCGCCCC CCTGACGAGC colE1 ~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~ 3721 ATCACAAAAA TCGACGCTCA AGTCAGAGGT GGCGAAACCC GACAGGACTA TAAAGATACC colE1 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~ 3841 GATACCTGTC CGCCTTTCTC CCTTCGGGAA GCGTGGCGCT TTCTCATAGC TCACGCTGTA colE1 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~ 3961 TTCAGCCCGA CCGCTGCGCC TTATCCGGTA ACTATCGTCT TGAGTCCAAC CCGGTAAGAC colE1 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ... ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~ 4081 GCGGTGCTAC AGAGTTCTTG AAGTGGTGGC CTAACTACGG CTACACTAGA AGAACAGTAT colE1 ~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~ 4141 TTGGTATCTG CGCTCTGCTG AAGCCAGTTA CCTTCGGAAA AAGAGTTGGT AGCTCTTGAT colE1 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 4201 CCGGCAAACA AACCACCGCT GGTAGCGGTG GTTTTTTTGT TTGCAAGCAG CAGATTACGC colE1 ~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 4261 GCAGAAAAAA AGGATCTCAA GAAGATCCTT TGATCTTTTC TACGGGGTCT GACGCTCAGT 4321 GGAACGAAAA CTCACGTTAA GGGATTTTGG TCATGAGATT ATCAAAAAGG ATCTTCACCT 4381 AGATCCTTTT AAATTAAAAA TGAAGTTTTA AATCAATCTA AAGTATATAT GAGTAAACTT 4441 GGTCTGACAG TTATTAGAAA AATTCATCCA GCAGACGATA AAACGCAATA CGCTGGCTAT ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~ KanR 4501 CCGGTGCCGC AATGCCATAC AGCACCAGAA AACGATCCGC CCATTCGCCG CCCAGTTCTT ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ KanR 4561 CCGCAATATC ACGGGTGGCC AGCGCAATAT CCTGATAACG ATCCGCCACG CCCAGACGGC ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~ KanR 4621 CGCAATCAAT AAAGCCGCTA AAACGGCCAT TT TCCACCAT AATGTTCGGC AGGCACGCAT ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~ KanR 4681 CACCATGGGT CACCACCAGA TCTTCGCCAT CCGGCATGCT CGCTTTCAGA CGCGCAAACA ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ KanR 4741 GCTCTGCCGG TGCCAGGCCC TGATGTTCTT CATCCAGATC ATCCTGATCC ACCAGGCCCG ~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~ KanR 4801 CTTCCATACG GGTACGCGCA CGTTCAATAC GATGTTTCGC CTGATGATCA AACGGACAGG ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ KanR 4861 TCGCCGGGTC CAGGGTATGC AGACGACGCA TGGCATCCGC CATAATGCTC ACTTTTTCTG ~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~ KanR 4921 CCGGCGCCAG ATGGCTAGAC AGCAGATCCT GACCCGGCAC TTCGCCCAGC AGCAGCCAAT ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ KanR 4981 CACGGCCCGC TTCGGTCACC ACATCCAGCA CCGCCGCACA CGGAACACCG GTGGTGGCCA ~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~ KanR 5041 GCCAGCTCAG ACGCGCCGCT TCATCCTGCA GCTCGTTC AG CGCACCGCTC AGATCGGTTT ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~ KanR 5101 TCACAAACAG CACCGGACGA CCCTGCGCGC TCAGACGAAA CACCGCCGCA TCAGAGCAGC ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ KanR 5161 CAATGGTCTG CTGCGCCCAA TCATAGCCAA ACAGACGTTC CACCCACGCT GCCGGGCTAC ~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~ KanR 5221 CCGCATGCAG GCCATCCTGT TCAATCATAC TCTTCCTTTT TCAATATTAT TGAAGCATTT ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~ Kan R 5281 ATCAGGGTTA TTGTCTCATG AGCGGATACA TATTTGAATG TATTTAGAAA AATAAACAAA 5341 TAGGGGTTCC GCGCACATTT CCCCGAAAAG TGCCACCTAA ATTGTAAGCG TTAATATTTT 5401 GTTAAAATTC GCGTTAAATT TTTGTTAAAT CAGCTCATTT TTTAACCAAT AGGCCGAAAT 5461 CGGCAAAATC CCTTATAAAT CAAAAGAATA GACCGAGATA GGGTTGAGTG GCCGCTACAG 5521 GGCGCTCCCA TTCGCCATTC AGGCTGCGCA ACTGTTGGGA AGGGCGTTTC GGTGCGGGCC 5581 TCTTCGCTAT TACGCCAGCT GGCGAAAGGG GGATGTGCTG CAAGGCGATT AAGTTGGGTA T7 promoter ~~~ ~~~~~~~~~~~~~~~~~ 5641 ACGCCAGGGT TTTCCCAGTC ACACGCGTAA TACGACTCAC TATAG

权利要求:
Claims (14)
[0001]
1. Self-replicating RNA molecule characterized by the fact that it comprises a polynucleotide that is encoded by a DNA molecule that comprises: a. b. the sequence of SEQ ID NO: 35; c.UL128 sequence of SEQIDNO: 43; d.UL130 sequence of SEQIDNO: 45; and sequenceUL131 of SEQ ID NO: 47 in which the gH sequence, the gL sequence, the 128 sequence, the UL130 sequence and the UL131 sequence are operationally linked to one or more control elements so that , when the self-replicating RNA molecule is introduced into a suitable cell, the gH, gL, UL128, UL130 and UL131 proteins are produced in an amount sufficient to form a complex in the cell containing the gH, gL, UL128, UL130 proteins and UL131.
[0002]
2. Self-replicating RNA molecule according to claim 1, characterized by the fact that each of the control elements is selected independently from the group consisting of a subgenomic promoter, an IRES and a 2A viral site.
[0003]
3. Self-replicating RNA molecule according to claim 1 or 2, characterized by the fact that the herpesvirus is cytomegalovirus (CMV).
[0004]
4. Self-replicating RNA molecule according to claim 3, characterized by the fact that the first protein or fragment is gH or a fragment thereof, the second protein or fragment is gL or a fragment thereof, the third protein or fragment is UL128 or a fragment thereof, the fourth protein or fragment is UL130 or a fragment thereof and the fifth protein or fragment is UL131 or a fragment thereof.
[0005]
5. Self-replicating RNA molecule according to any one of claims 1 to 4, characterized in that the self-replicating RNA molecule is an alphavirus replicon.
[0006]
6. Alphavirus replicon (VRP) particle characterized by the fact that it comprises the alphavirus replicon as defined in claim 5.
[0007]
7. Composition characterized by the fact that it comprises a VRP, as defined in claim 6 and a pharmaceutically acceptable vehicle.
[0008]
8. Composition according to claim 7, characterized by the fact that it still comprises an adjuvant.
[0009]
Composition comprising the fact that it comprises self-replicating RNA as defined in any one of claims 1 to 5 and a pharmaceutically acceptable carrier.
[0010]
10. Composition according to claim 9, characterized by the fact that it still comprises an RNA release system.
[0011]
11. Composition according to claim 10, characterized by the fact that the RNA release system comprises: (i) a liposome, (ii) a polymeric nanoparticle, (iii) a cationic oil-in-water nanoemulsion, or (iv) any combination thereof.
[0012]
12. Composition according to claim 11, characterized by the fact that the delivery system comprises a cationic oil-in-water nanoemulsion.
[0013]
13. Recombinant DNA molecule characterized by the fact that it encodes the self-replicating RNA molecule as defined in any one of claims 1 to 5.
[0014]
Use of the self-replicating RNA molecule, as defined in any one of claims 1 to 5, or of VRP as defined in claim 6, or the composition as defined in any of claims 7 to 12, characterized in that it is to prepare a drug to induce an immune response in an individual against herpesvirus.

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同族专利:

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公开号 | 公开日

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AU2011316707A1|2013-05-09|

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EP2627351B1|2018-12-26|

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CA2814386C|2019-08-20|

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AU2016238966A1|2016-11-03|

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ES2716243T3|2019-06-11|

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AU2016238966B2|2018-08-16|

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MX363307B|2019-03-20|

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CA2814386A1|2012-04-19|

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US20140030292A1|2014-01-30|

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RU2013121582A|2014-11-20|

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CN103269713A|2013-08-28|

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JP2017205126A|2017-11-24|

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JP2013544504A|2013-12-19|

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KR102162111B1|2020-10-07|

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KR20200119880A|2020-10-20|

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WO2012051211A3|2012-06-07|

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ZA201302548B|2014-09-25|

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EP2627351A2|2013-08-21|

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MX2013003939A|2013-10-17|

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US20190144507A1|2019-05-16|

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KR102266691B1|2021-06-23|

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RU2597974C2|2016-09-20|

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TR201903651T4|2019-04-22|

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WO2012051211A2|2012-04-19|

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JP2016096827A|2016-05-30|

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EP3520813A1|2019-08-07|

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CL2013000984A1|2013-10-11|

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BR112013008700A2|2016-06-21|

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CN103269713B|2016-01-20|

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US11078237B2|2021-08-03|

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KR20130117781A|2013-10-28|

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法律状态:
2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2018-04-03| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2019-07-02| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

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2019-10-22| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2020-04-22| B06A| Notification to applicant to reply to the report for non-patentability or inadequacy of the application [chapter 6.1 patent gazette]|

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2020-12-01| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-03-02| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 11/10/2011, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US39196010P| true| 2010-10-11|2010-10-11|

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US61/391,960|2010-10-11|

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PCT/US2011/055834|WO2012051211A2|2010-10-11|2011-10-11|Antigen delivery platforms|

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