Streptococcus pyogenes 1314 Colonization of tissues by S. pyogenes is thought to result from a failure in the constitutive defenses (normal flora and other nonspecific defense mechanisms) which allows establishment of the bacterium at a portal of entry (often the upper respiratory tract or the skin) where the organism multiplies and causes an inflammatory purulent lesion (Textbook of Bacteriology). Group A streptococcal infections, Strep throat, Scarlet fever Macrophages and the antibody mediated response are the major defenses for host protective immunity against S. pyogenes infection (Textbook of Bacteriology). S. pyogenes is a human pathogen and mice are the animal model that is used (Okamoto et al., 2005). Streptococcus pyogenes is a spherical gram-positive bacterium that grows in long chains and is the cause of Group A streptococcal infections. S. pyogenes displays streptococcal group A antigen on its cell wall. S. pyogenes typically produces large zones of beta-hemolysis (the complete disruption of erythrocytes and the release of hemoglobin) when cultured on blood agar plates and are therefore also called Group A (beta-hemolytic) Streptococcus (abbreviated GAS). S. pyogenes is the cause of many important human diseases ranging from mild superficial skin infections to life-threatening systemic diseases. Infections typically begin in the throat or skin. Examples of mild S. pyogenes infections include pharyngitis ("strep throat") and localized skin infection ("impetigo"). Erysipelas and cellulitis are characterized by multiplication and lateral spread of S. pyogenes in deep layers of the skin. S. pyogenes invasion and multiplication in the fascia can lead to necrotizing fasciitis, a potentially life-threatening condition requiring surgical treatment (Wiki: S. pyogenes). Baboon Papio cynocephalus 9556 Bank vole Clethrionomys glareolus 447135 Bear Ursus americanus 9643 Birds Passeroidea 175121 Brown Trout Salmo trutta 8032 Buffalo Bison bison 9901 Carnivores Vulpes 9625 Cat Felis catus 9685 Catfishes Siluriformes 7995 Cattle Bos taurus 9913 Chicken Gallus gallus 9031 Chimpanzee Pan troglodytes 9598 chinchillas Chinchillidae 10150 Copper Pheasant Syrmaticus soemmerringii 9067 Deer Cervus elaphus 9860 Deer mouse Peromyscus maniculatus 10042 Dog Canis familiaris 9615 Ducks Anas 8835 Ferret Mustela putorius furo 9669 Fish Hyperotreti 117565 Gerbil Gerbillina 10045 Goat Capra hircus 9925 Gray wolf Canis lupus 9612 Guinea pig Cavia porcellus 10141 Hamster Mesocricetus auratus 10036 Horse Equus caballus 9796 Human Homo sapiens 9606 Macaque Macaca fascicularis 9541 Mongolian Gerbil Meriones unguiculatus 10047 Monkey Platyrrhini 9479 Mouse Mus musculus 10090 None None Parrot Psittacidae 9224 Pig Sus scrofa 9823 Rabbit Oryctolagus cuniculus 9986 Rainbow trout Oncorhynchus mykiss 8022 Rat Rattus 10114 Raven Corvus corax 56781 sei whale Balaenoptera borealis 9768 Sheep Ovis aries 9940 Squirrel Spermophilus richardsonii 37591 Tree shrew Tupaiidae 9393 Trouts, salmons & chars Salmoninae 504568 Turkey Meleagris gallopavo 9103 Vole Microtus ochrogaster 79684 Water buffalo Bubalus bubalis 391902 Group A streptococcal recombinant fusion peptide Vaccine VO_0004247 Subunit vaccine Clinical trial Intramuscular injection (i.m.) A recombinant fusion peptide group A streptococcal vaccine containing N-terminal M protein fragments from serotypes 1, 3, 5, 6, 19, and 24 (Kotloff et al., 2004). Intramuscular injection (i.m.) Vaccination elicited 4-fold or more increases in 40 (83%) of 48 possible assays (ie, 6 antigens × 8 volunteers) following the 50-µg dose, in 45 (75%) of 60 possible assays (ie, 6 antigens × 10 volunteers) following the 100-µg dose, and in 57 (95%) of 60 possible assays (ie, 6 antigens × 10 volunteers) following the 200-µg dose. The geometric mean antibody titer following vaccination was significantly higher than the prevaccination titer for each antigen measured in all dose groups (Kotloff et al., 2004). Twenty-eight healthy adults aged 18 to 50 years were vaccinated. Groups of volunteers received 3 spaced intramuscular injections of either 50-µg (n = 8), 100-µg (n = 10), or 200-µg (n = 10) doses of vaccine into the deltoid muscle of alternating arms. Escalation to a higher dose level required approval by an independent data and safety monitoring committee that reviewed all data from recipients of the lower dose group collected between day 0 until 14 days after the third inoculation. A day 0, 28, and 56 dosing schedule was chosen initially. When 1 of 8 recipients of a 50-µg dose experienced moderate induration and pruritus at the injection site following the third injection, the sponsor and independent data and safety monitoring committee recommended that the dosing schedule for subsequent groups be changed to 0, 28, and 112 days (Kotloff et al., 2004). Vaccination was well-tolerated. Local erythema, swelling, or tenderness were detected in 6 (21%) of 29 participants within 7 days after the first inoculation and 12 (43%) of 28 participants each after the second and third inoculations. All local reactions were graded as mild (≤30 mm and easily tolerated) with the exception of the aforementioned participant who developed moderate (31-80 mm) erythema, swelling, and itching for 1 day after the third dose of 50 µg (Kotloff et al., 2004). licensed Group A streptococcal infection human vaccine Generic Unknown VO_0002852 Subunit vaccine Licensed A generic representation of vaccines used to prevent Group A streptococcal infections in humans, most commonly based on purified protein subunits such as the M protein or its derivatives. These vaccines aim to elicit protective immunity without using whole bacteria or live components. S. pyogenes FbaA Protein Vaccine VO_0004054 Subunit vaccine Research subcutaneous injection Freund’s adjuvant subcutaneous injection Purified FbaA protein Recombinant protein preparation BALB/c Mice were immunized subcutaneously with purified FbaA + Freund’s adjuvant at weeks 0, 2, and 4 (Ma et al., 2009). 60% of mice immunized with FbpA were protected from challenge with group A streptococcus (Ma et al., 2009). Mice immunized with FbaA or PBS were injected i.p. with 1 ml bacterial suspension (equivalent to 2 × 10^8 CFU) and monitored survival daily for 15 days (Ma et al., 2009). Assay for immune response showed that FbaA could induce protein-specific high serum IgG titer in BALB/c mice 10 days after injection. There was no significant difference between the antibody titers of the FbaA vaccine and an M protein vaccine, which is the best immugen of group A streptococcus, and FbaA induced significantly higher titers than PBS-vaccinated mice (Ma et al., 2009). S. pyogenes FBP54 Protein Vaccine VO_0004055 Subunit vaccine Research Orally Orally Recombinant FBP54 protein Recombinant protein preparation BALB/c Mice were orally immunized with cholera toxin (CT; 10 μg)-FBP54 (10 μg) or CT (10 μg)-PBS by using an intubation needle. Immunization was performed four times, on days 0, 14, 28, and 42 (Kawabata et al., 2001). Mice subcutaneously or orally immunized with FBP54 survived significantly longer following the challenge with S. pyogenes than did nonimmunized mice (Kawabata et al., 2001). Actively immunized mice were intraperitoneally challenged with an appropriate number of CFU of S. pyogenes SSI-1 (M3), SSI-9 (M1), or S42 (M12) on day 51 following immunization (Kawabata et al., 2001). An enzyme-linked immunosorbent assay revealed that antigen-specific IgG antibodies were induced in the sera of immunized mice, while high salivary levels of IgA antibodies were detected after oral and nasal immunizations. Nonimmunized control groups did not show any detectable humoral immune responses to FBP54 in sera (Kawabata et al., 2001). An enzyme-linked immunosorbent assay revealed that antigen-specific IgG antibodies were induced in the sera of immunized mice, while high salivary levels of IgA antibodies were detected after oral and nasal immunizations. Nonimmunized control groups did not show any detectable humoral immune responses to FBP54 in sera (Kawabata et al., 2001). S. pyogenes M Protein Vaccine VO_0004053 Subunit vaccine Research intranasal immunization 10 μg of CTB or 0.5 μg of the TLR2/6 agonist MALP-2 as mucosal adjuvants (Schulze et al., 2006). intranasal immunization A polypeptide encompassing a conformational B cell epitope of the M protein conjugated with DT (Schulze et al., 2006). Recombinant protein preparation A polypeptide encompassing a conformational B cell epitope of the M protein (J8, positions 344–355 of the M1 sequence, accession no. X62131) was synthesised, purified and conjugated with DT (Schulze et al., 2006). BALB/c Mice were immunised by intranasal route (10 μl per nostril) with either J8-DT (M protein) (30 μg per dose) co-administered with 10 μg of CTB or 0.5 μg of the TLR2/6 agonist MALP-2 as mucosal adjuvants, on day 0, 7, 14, and 28. Control animals received PBS alone (Schulze et al., 2006). Mice immunized with J8-DT had 60% survival following challenge (Schulze et al., 2006). Mice were intranasally challenged with 10^8 CFU of the heterologous virulent S. pyogenes strain NS192 in 40 μl of PBS (20 μl per nostril) (Schulze et al., 2006). S. pyogenes SfbI Protein Vaccine VO_0004056 Subunit vaccine Research intranasal immunization Cholera toxin B subunit intranasal immunization Recombinant SfbI protein Recombinant protein preparation BALB/c MIce were immunized intranasally with 20 μL of SfbI (H2 fragment) covalently coupled to CTB or with CTB alone as a control on days 1, 3, 5, and 26 (30 mg/dose) (Guzmán et al., 1999). SfbI-vaccinated animals showed 80% and 90% protection against homologous and heterologous challenge (Guzmán et al., 1999). On day 36 mice were challenged with 10^6 cfu of S. pyogenes DSM 2071 or NS239, respectively (Guzmán et al., 1999). S. pyogenes Sib35 Protein Vaccine VO_0004057 Subunit vaccine Research subcutaneous injection Freund's complete adjuvant subcutaneous injection Recombinant Sib35 protein Recombinant protein preparation BALB/c, C3H/HeN, C57/BL6 and CD1 Six-week-old female mice were separated into two groups, which were either subcutaneously immunized with rSib35 (50 μg) in Freund's complete adjuvant or injected with PBS in FCA on day 0, and given booster injections with rSib35 and Freund's incomplete adjuvant on days 14, 28, and 42 (Okamoto et al., 2005). The survival rates of all four-mouse strains were significantly increased by Sib35 vaccination. 100% of the Sib35-immunized C3H/HeN mice survived the potentially lethal GAS challenge, whereas all non-vaccinated C3H/HeN mice died after the challenge (Okamoto et al., 2005). Actively immunized mice were intraperitoneally challenged with an appropriate number of CFUs of strain SSI-1 on day 56 following primary immunization (Okamoto et al., 2005). Immunization of mice with Sib 35 induced significantly higher antigen-specific IgG antibodies in their sera beginning 28 days after immunization as compared to non immunized control mice (Okamoto et al., 2005). SL3261 expressing streptococcal M protein VO_0004676 Recombinant vector vaccine Research Intramuscular injection (i.m.) The aroA strain of S. typhimurium SL3261 was transformed with a low-copy plasmid vector pMK207, which contains the cloned gene spm5 encoding streptococcal M protein, the major virulence factor of these organisms (Poirier et al., 1988). Intramuscular injection (i.m.) Mice were immunized orally with the pMK207-transformed Salmonella SL3261 (Poirier et al., 1988). . VO_0003057 The orally immunized mice were completely protected against both intranasal and intraperitoneal challenge infections with virulent S. typhimurium SL1344 or M5 streptococci (Poirier et al., 1988). Immunized and control mice were challenged intraperitoneally with either the homologous M5 or heterologous M24 streptococci, or with wild-type S typhimurium SL1344 (Poirier et al., 1988). emm1 Streptococcus pyogenes VO_0012397 311757 311758 CAA44062.1 2OTO CDD:273479 CDD:291694 CDD:295219 CDD:279132 GOA:Q10372 HSSP:1IC2 InterPro:IPR001899 InterPro:IPR005877 InterPro:IPR019931 InterPro:IPR019948 InterPro:IPR019950 UniProtKB/TrEMBL:Q10372 1314 ? M protein type 1 6.86 52910.57 546 Gram-positive signal peptide, YSIRK family; TIGR01168 >gi|311757|emb|X62131.1| S.pyogenes emm1 (29/58) gene for M protein type 1 GGATCCAATGATAACATAAGGAGCATAAAAATGGCTAAAAATAACACGAATAGACACTATTCGCTTAGAA AATTAAAAACAGGAACGGCTTCAGTAGCGGTAGCTTTGACTGTTTTAGGGGCAGGTTTTGCGAATCAAAC AGAGGTTAAGGCTAACGGTGATGGTAATCCTAGGGAAGTTATAGAAGATCTTGCAGCAAACAATCCCGCA ATACAAAATATACGTTTACGTCACGAAAACAAGGACTTAAAAGCGAGATTAGAGAATGCAATGGAAGTTG CAGGAAGAGATTTTAAGAGAGCTGAAGAACTTGAAAAAGCAAAACAAGCCTTAGAAGACCAGCGTAAAGA TTTAGAAACTAAATTAAAAGAACTACAACAAGACTATGACTTAGCAAAGGAATCAACAAGTTGGGATAGA CAAAGACTTGAAAAAGAGTTAGAAGAGAAAAAGGAAGCTCTTGAATTAGCGATAGACCAGGCAAGTCGGG ACTACCATAGAGCTACCGCTTTAGAAAAAGAGTTAGAAGAGAAAAAGAAAGCTCTTGAATTAGCGATAGA CCAAGCGAGTCAGGACTATAATAGAGCTAACGTCTTAGAAAAAGAGTTAGATACGATTACTAGAGAACAA GAGATTAATCGTAATCTTTTAGGCAATCGAAAACTTGAACTTGATCAACTTTCATCTGAAAAAGAGCAGC TAACGATCGAAAAAGCAAAACTTGAGGAAGAAAAACAAATCTCAGACGCAAGTCGTCAAAGCCTTCGTCG TGACTTGGACGCATCACGTGAAGCTAAGAAACAGGTTGAAAAAGATTTAGCAAACTTGACTGCTGAACTT GATAAGGTTAAAGAAGACAAACAAATCTCAGACGCAAGCCGTCAAGGCCTTCGCCGTGACTTGGACGCAT CACGTGAAGCTAAGAAACAGGTTGAAAAAGATTTAGCAAACTTGACTGCTGAACTTGATAAGGTTAAAGA AGAAAAACAAATCTCAGACGCAAGCCGTCAAGGCCTTCGCCGTGACTTGGACGCATCACGTGAAGCTAAG AAACAAGTTGAAAAAGCTTTAGAAGAAGCAAACAGCAAATTAGCTGCTCTTGAAAAACTTAACAAAGAGC TTGAAGAAAGCAAGAAATTAACAGAAAAAGAAAAAGCTGAACTACAAGCAAAACTTGAAGCAGAAGCAAA TGTACTTAAAGATCCATTAGCGAAACAAGCTGAAGAACTCGCAAAACTAAGAGCTGGAAAAGCATCAGAC TCACAAACCCCTGATACAAAACCAGGAAACAAAGCTGTTCCAGGTAAAGGTCAAGCACCACAAGCAGGTA CAAAACCTAACCAAAACAAAGCACCAATGAAGGAAACTAAGAGACAGTTACCATCAACAGGTGAAACAGC TAACCCATTCTTCACAGCGGCAGCCCTTACTGTTATGGCAACAGCTGGAGTAGCAGCAGTTGTAAAACGC AAAGAAGAAAACTAAGCTGAATTC >CAA44062.1 M protein type 1 [Streptococcus pyogenes] MAKNNTNRHYSLRKLKTGTASVAVALTVLGAGFANQTEVKANGDGNPREVIEDLAANNPAIQNIRLRHEN KDLKARLENAMEVAGRDFKRAEELEKAKQALEDQRKDLETKLKELQQDYDLAKESTSWDRQRLEKELEEK KEALELAIDQASRDYHRATALEKELEEKKKALELAIDQASQDYNRANVLEKELDTITREQEINRNLLGNR KLELDQLSSEKEQLTIEKAKLEEEKQISDASRQSLRRDLDASREAKKQVEKDLANLTAELDKVKEDKQIS DASRQGLRRDLDASREAKKQVEKDLANLTAELDKVKEEKQISDASRQGLRRDLDASREAKKQVEKALEEA NSKLAALEKLNKELEESKKLTEKEKAELQAKLEAEANVLKDPLAKQAEELAKLRAGKASDSQTPDTKPGN KAVPGKGQAPQAGTKPNQNKAPMKETKRQLPSTGETANPFFTAAALTVMATAGVAAVVKRKEEN Protective antigen Mice were intranasally immunized with diphtheria toxoid (DT) conjugated polypeptides encompassing a conformational-constrained B cell epitope of the M1 protein (J8). Vaccinated mice were challenged 10 days after the last boost by the intranasal route. Animals had 60% protection against challenge [Ref1510:Schulze et al., 2006]. fbaA Streptococcus pyogenes SSI-9 VO_0012396 14915682 CDD:273479 CDD:320995 CDD:273478 1314 ? fibronectin-binding protein 4.73 36233.27 427 Gram-positive signal peptide, YSIRK family; TIGR01168 >BAB62098.1 fibronectin-binding protein [Streptococcus pyogenes] MRRAENNKHSRYSIRKLSVGVTSIAIASLFLGKVAYAVDGIPPISLTQKTTATTSENWHHIDKDGLIPLG ISLEAAKEEFKKEVEESRLSEAQKETYKQKIKTAPDKDKLLFTYHSEYMTAVKDLPASTESTTQPVEAPV QETQASASDSMVTGDSTSVTTDSPEETPSSESPVAPALSEAPAQPAESEEPSVAASSEETPSPSTPAAPS TPAAPETPEEPAAPSQPAESEESSVAATTSPSPSTPAESETQTPPAVTKDSDKPSSAAEKPAASSLVSEQ TVQQPTSKRSSDKKEEQEQSYSPNRSLSRQVRAHESGKYLPSTGEKAQPLFIATMTLMSLFGSLLVTKRQ KETKK Protective antigen Mice immunized with FbpA were protected from challenge with group A streptococcus [Ref1509:Ma et al., 2009]. fbp54 Streptococcus pyogenes AAR18990 CDD:224212 CDD:283353 1314 fibronectin/fibrinogen-binding protein 8.52 52434.05 567 Predicted component of the ribosome quality control (RQC) complex, YloA/Tae2 family, contains fibronectin-binding (FbpA) and DUF814 domains [Translation, ribosomal structure and biogenesis]; COG1293 >AAR18990.1 fibronectin/fibrinogen-binding protein, partial [Streptococcus pyogenes] MIMRKYLQGAVIEQLEQIDNDRIIEIKVSNKNEIGDAIQATLIIEIMGKHSNIILVDRAENKIIESIKHV GFSQNSYRTILPGSTYIEPPKTAAVNPFTITDVPLFEILQTQELTVKSLQQHFQGLGRDTAKELAELLTT DKLKRFREFFARPTQANLTTASFAPVLFSDSHATFETLSDMLDHFYQDKAERDRINQQASDLIHRVQTEL DKNRNKLSKQEAELLATENAELFRQKGELLTTYLSMVPNNQDSVVLDNYYTGEKLEIALDKALTPNQNAQ RYFKKYQKLKEAVKHLSGLIADTKQSITYFESVDYNLSQASIDDIEDIREELYQAGFLKSRQRDKRHKRK KPEQYLASDGKTILMVGRNNLQNEELTFKMAKKGELWFHAKDIPGSHVIIKDNLDPSDEVKTDAAELAAY YSKARLSNLVQVDMIEAKKLHKPSGAKPGFVTYTGQKTLRVTPDQAKILSMKLF Protective antigen [Ref4815:Kawabata et al., 2001] IgA Mus musculus 238447 AC160982 10090 12 8607 12639 - immunoglobulin heavy constant alpha Also known as IgA; Igh-2 >gi|121699722:8607-12639 Mus musculus immunoglobulin heavy chain complex (Igh) on chromosome 12 AGTACTGGGGGACCTCTTTGCTGCCAAACGGGCCTCGAACAGTTGTAACAGTGAGTGCTGTGCTGTAGAA CAAGCTCAGTAGGAAGAGGGTGAGGAAGGTCACAGTGGTGGGCCACAGGCTGGCACCTGGGGCCTCTTCC TCCAGGATGTCTTCTGACTGGTCCAGTAGCACATAGGAAAGTGGCTCTTGACGTTCTGTAAGACATAGAT GACCTTCTAGATCCAAACCCATGGGGATGGGGGCTCAGACTTAAGGTTTCTGCTTCTATGCCTCCTTGGG CTTTGGGGACAGTGGTGGTAGGGGTCCCTTATTCCCGGGAAGGGACTTGTTCAGGGATAATGAGGAGGCA GGGTCCCAGGTAAGGGACTGGAATCCCAGCAGTTCTTGAGATGGCCCCAAGACCCATCTCTCTCTCTTAG GGAAACCTTAATTAGAGACCTGTCATGGTAAGAGAGTTGTTTCTGTCAAACTCTGAGAAGAGTTTGAACC CAAGGCTCCTTAGGTCTCAGTCCTTTCTAGATATTTAGCAATACCTCCCTAAACCCCAGTTCTTAGGCTA ATCTTGGCTTGGGTACTAGGGTTGTGTAAGATCAGACACCTTCAAACAGATACAGGCCAATGTGATTTCT GGGCCAAAGTTAGACTACCAAGGCCTGGACATGTGGTCAGAGGACTCTGTTGCATTCTTAAGAGCTGTGA CTGGGGGTTAAGCAACAGTAAAGACCCCCAGTAGAGCCAACCCTGCTGTCCTCAGGTTCTCTGCGCACAG AGTTTCATTTTAAGTGGCAGTAGGAAATGTGTACTGATAGTCAACCACTCGTATTTCTGTCACTGCAGCC ATCCATCAATCCATCCATCATCCCCATCGTTCATCCTTGTAGCCAGCCATCCATTACCCTCCAGCCGCTC ACTCATCATCTTTCCCGACTATCGTGATTCTCCAGCTTCTCTGCCCCCTCTCCCTGTGGGGATTCAGTCT TTCACCTATTGACTCCTCCTTACTAGGATTCTCTGTCATGGGCCAGGCCTTGGATTCCATGGGTGGCTAT GGTACTTTTCTGAGTCAGGTTTCCCAAGCTGGTCTGTTGCTCTTGCTATTCTCAGGGAACTGGACTTTCA AGCTGGAGAGTATCCAGGGCATGCATGGGCCTTTACTCCACTCTTGCTCTGAGAGCAGAGGGAAGTTGCT AGAAACCAGCAACTCCTCCCCCCCCCCCCCGAAGTTCTGAAGGCCTGTGAGACAGGAGCAGGGCCCCCAC TGCCCTCTTGTGGACACCTGGGCTCCAAGTATACCTGGTTGTAGAACTTTGTGTTCTAGGGGTGCCCATG GAGGAGGCCGAGGCCTGTGTGGGAGTGGTCTCCATGGCCTGCTCCTGCTTCTTCCCAGATTTGCCTCTTA TCCTGCTTCTGGTTTGTGATACTTGGGCTCAGGATGGGAAGGGAGACTTAGGTTAGAAAGGGGGCACCTG GAGGGGCCTATGCCCTTGTCCATTGTGTGTAGTTGTCAGTGTCGGGCCTGGAAATTCTCCCGGGGGCTTG GAGGGGACTCCCCTTGCTTTCCAGAAGCTGGGTGTGGGCTGTGAACTTCATCTTCCTCCAGGGTTCAGGT CTGTGTGAGTGTGCAAATGTGAGTGTCTGTGCATGTATGCCCATGTGCATGTATGCAGAACAGGGTGTAT GCCCATGTGCATGTGTGAAGAGCAGGGTGCTGCTGAGGGTTGTCTGTGCCATGCTATATGTCTTTCTCAT GAGTCAGTGGTCACCCTGAATGCATGTTTCCATTCAGGGATGGCCTACTGAGGGTGCGTGGCATCTTCTT CCCAGTGCCCCTGTGTTCATCCCTTCATTCTCATACCATCATCTCTATTGTGACCCCCACACGGCACCAG CCTTGATGGTGCTACCCTTTTGCTCCATCTATCCCTGTCTTGTTTGGGTTAGAAGCTGCGGTCTAATAAA CAGCCACACCACCCACCACTCAGAGTACTTGTGCAGCAACCCACTGCCCTGGGGACTCTCCCATGAGCTT TGCCTTCTTGGCTGAGTCTGCTCGCCTTGGATTTCATCCCCAGTTTATTCTTACTTCCCATTCACTCATT GCACATTCACAGGGCAGGTGCACACACTCTCATGTTTCCACCAACATGAACACACATAGATATATGCATG CTCATAGGTATGCACAGGCACACACTTGCTCACAGGGACATAGATATAGTGTGTCCACATATGTACTTAT ACCCATATACATACCTATAAACCATAGGTGCACACAAACTCACTCCTCTCTTGCTGCACACAGGTACACA CATGAAGGCACATGGACCCATCCATAAGCACTCACCAATACATAGACATGCATACACATATACTCTAGGC ATGAAGGGTCTTCAAAGTCTCCGAGGCCTTACAAGCTTAGGTGGTGGTGTTTCTCCCTCCCTGGGCCCTG ACCCCTCCCTGTGTTCTGTAGACCCTAAGGATGATGGACAGGCACTGGATGGAAGTGCAGGGATACTTTG GATGAGCACAGAGTTTATTTCAGGAGTAGGGACAGGCAGGGTGGCTCAGTAGCAGATGCCATCTCCCTCT GACATGATCACAGACACGCTGACATTGGTGGGTTTACCCGACAGACGGTCGATGGTCTTCTGGGTGAAGT TCATGGGCAAGGCCTCGTGGCCCACCATGCAGGAGTACTGGTCACCCTGTTTCCAGAGTTCAGCTGATAC ACGCAACACGCTTGTCACCAGGTAGGTGGTGGCTCCCTCGCCTGGCTCCTTTAGGGGCTCAAACACTAGG TAGCTTTCTGGGGACAGCTCCTCATTTCCATGCAGCCATCGCACCAGCACTTCTTTAGGGTTGAAAGCTC GCACCAGGCATGTCAGGGACACGAGCTCATTCAGGGCCAGCTCCTCCGACGGCGGCGGTAGCAGGTGGAC CTGGGGTGGGAAGGTGTTCACTGGAAGGTAGAAAGAAGAGTTATGGCTCAGACAAGGAGAGCAAGACCCC TCTGCCCTTCCCTTCTGGGCAGTTCCTCAGATAGCTCCAATTTCCCTCTGTGATATAAGGACAGGAGCAG TTAGTTGAGCATCTGTATTATAGGAAGAAAGCAGGCATGTGAGCAGGGAACGTCATACAATGTCCCGGGT ATGCATCTGGGCTCACCTGTGATTTTGGCAATTGTGCCAGTTAAGGTGTCAGACTCAGGATGGGTAACTG TGCACTTGAATGATGCGCCACTGTTCCAGCGCTCAGCACAGCCAGGCAGGACGCTGGACACACTGTAGCA GCCGCAGGAATTCTGCACAGCTTTCTTCTGCACTGCATCCTTCCCAGTGGAGGGCTCCCAGGTGAAGACA GCTCCCTCAGGATTTCTCAGGCCATTCAGAGTACATGTGAGGCTGGCATCTGAACCCAGGAGCAGGTCCT CAAGAGCTGGCCGCTGCAGTGACAGGCTGGGATGGCAGGAAGGAGGACAAGGAGGACAAGGAGGAGGAGG ACCTGTAACAGAGAAGTCCTAGCAAATCAGTATATTCTCCTTTTCTCCTTTGCTGTCCCCTTTTCTGGAT GTTCTGAGGCCTCAGTTCCTTATGGCCTGTTTACGCTTCCCTTCCCCCACCCCCATGGGAGGTTTCTGAG GGTCCCTGTGAGGGTGTGCCTCAGAGGGATATATGGATCTAGATAAGGTAGAACTTATCCCACCCCCAGC TGACCCCCTAACGTTCTTTACCAGAGCACTTCACATCCAATTCTTGGACGGCGTTAGAGTCATGTTGCAC GGAACATTTCACGGATTCTCCTTCTGGGCACTCGACAGCTGGCAGGGTCAACTGGCTGCTCATGGTGTAC CCTCCCCCAGAGGCCAGGGCAGGTGGGAAGTTTACGGTGGTTATATCCTTCCCACTCTTTCCCCAGGTCA CATTCATCGTGCCGGAAGGGAAGTAATCGTGAATCAGGCAGCCGATTATCACTGGGTCACTTGACAGAGC TCGTGGGAGTGTCAGTGGGTAGATGGTGGGATTTCTCGCAGAC Vaximmutor IgG Mus musculus 16059 AF010213 10090 12 881411 914690 + immunoglobulin heavy chain (V7183 family) Also known as IgG; IgH; VI24H; VH7183; B9-scFv; IgVH1(VSG) >gi|94393741:881411-914690 Mus musculus strain 129/SvJ chromosome 12 unlocalized genomic contig, MGSCv37 alternate locus group 129/SvJ CATGGACTTTGGGCTCAGCTGTGTTTTCCTTGTCCTCATTTTAAGAGGTAATTTGTAGAAATAAGATCCT GCCAGTATTGTGTACAGGAGAAATAGAAAAATTTTTCTTTCCTCTATTTTGTTTTGTTTTGTTAGTGACA GTTTACAAATAAGCATTCTCTGTTGTGAGGTGCCCAGTGTGAGGTGAAGATGGTGGAGTCTGTGGGAGGC TTAGTGCAGCCTGTAGGGTCATTGAAACCCTCCTGTGCAGCCTCTGGATTCATTCTCACTGACTACTGAA TGACCTGGATCCTTCAGGCTTCAAAGAAAAGGATGGAGAGGGTGACAATAAAATTTTTCCCACTCACACC CACTTGCTGGCCCTGGCGTTCCCCTGTAATGAGGCACATAAAGTTTGCAAAACCAAGGGGCCTCTCTTCT CAATGATGGCTGACTAGGACATCTTCTGATACATATGCAGCTAGAGACATGAGCTCCCGGGATACTGGTT ACTTCATATTGTTGTTCCCCCACAACAGTTGCAGACCCTTTTATTTCTGTGGGTACTTTCACTAGCTCCT CCATTGGGGGCCCTGTGTTCCATCCAATAGCTGACTGTGAGCATCCACTTCTGTAGTTGCTAGGCCCCGG CATAGCCTCACAAGAGACAGCTATATCAGGGTCCTTTCAGCAAAATCTTGCTGGTGTATGCAATGGTGTC AGAGTTTGGAGTCTGATTATGGGATGGATCCCCAGGTATGGCAAACTCTAGATGGTCCATCCTTTCCCAA CAATAATTTTTAATGGTGGAGATAGCACCTACTATCCAGACACAATGAAGGGCCAATTCACTATCTCTAG AGATGATGCCAAAAACACACTTTACCTGAAAATAAACAGTCTGAGGTCTGAGTACACAGCCATGTATACA TATATTCCTAAGCTTGAGTAAGTGGACTTAAACTGATTCCATCACAACTTGCATGAGATGGATATTCCCC AGTGTTAAGACCTGTCACCATCACTGTCAATCAGAAGACAAAGTTTATGCACAACAAAACAAAAAAACCA AAAGCAGAGGCCTCCAATTACAAGTAATAGACCCAGACCCACAGTCTCTGAAAACTGACTGTACAGTTGG ATCCAGTCTTTTACTTCTTTTCCCTGGATTTTATATTACTGAGGAAATGAGGAAAGCTCTACAATATCTG TTCTCCATAGTGCTCAACACCTCCAAGCACAGGTTACCCATATTCATGCCTGCCTTCTGCTACACTTCTT GTCTTGTAGACTACTTCAACCTATTTTGTACTCCAGTTAATGAAACTCAAGTCTAGCAGCCTGTCACTGT TTATTCTAAAGTATTATGAACAGGTGACCTCCCATCCTTCCCCAACGCAATAATCATATTTAGGAATTTG AGGTTTTATGAGATATGATCTCAGGGTAGAGAGAGAAAGCAAACTACATAGAAATATAGACTGACATAAA TCAAGACTTGCATAAGCTAGTCCCCAAGTTCCATGTCCCTAAGTGGCAAGGACTATCTTCTGAGCCTAAT GAGATGAGATCCAAATCAAACCTCCTGGGTCTTTTTAGATAAACATGTGAGATCAATAGACTAAATGCTT TGGCTGGGCTTCCTTGCAATCCAATTCCCAAACAAAAATGGATCTGGCTCCACAGACACCACAAGAATAG TCTTAAATAGTTCTTTAAGTAGAATGTCTGATCACTACGAGCCCAATTCCATCCTAAATACTCTTCTGGA TTATACATAAATAAAAATTGAACATAGGGCATGGGGCACTGATCTCCCTGTGCTACATGAATGGGGGCTC ATTTACTAAATGTTCCCATTTTTCTTTCTAGCGCTGCACAGTGCAAATCCTACAACTTCCTGTTTATCTA CAATGTGAACTCCAAACAGTACAAGAAAAAACGTTCCTTATGTTCCTCTCCAGGTTCTCCAACAAGCACA GAGCAACCTTCTGTCACCAGGACGGAAAACTGGAAACCTTGCTCACTGCTTCCTTTTATTCCCTCGGGAA CCTCCCCCAATGCAAAGCAGCCCTCAGGCAGAGGATAAAAGCTCACACAAAGACGAGAAGCCCCATCCTC TTCTCATAGAGCATCCATCAGAGCATGGCTGTCCTGGGGCTGCTTCTCTGCCTGGTGACTTTCCCAAGCT GTAAGTGTTTCAGGGTTTCAGAAGAGGGACTAAGACATGTCAGCTAGAAGATGTGTGACTAATGGTGATG TTGCTTGTCCCCAGGTGTCCTGTCCCAGGTGCAGCTGAAGGAGTCAGGACCTGGCCTGGTGGCGCCCTCA CAGAGCCTGTCCATCACATGCACCGTCTCAGGGTTCTCATTAACTAGCTATGGTGTACACTGGGTTCGCC AGCCTCCAGGAAAGGGTCTGGAGTGGCTGGTAGTGATATGGAGTGATGGAAGCACAACCTATAATTCAGC TCTCAAATCCAGACTGAGCATCAGCAAGGACAACTCCAAGAGCCAAGTTTTCTTAAAAATGAACAGTCTC CAAACTGATGACACAGCCATGTACTACTGTGCCAGAAACACAGTGTGGGAAGTCCAATGTGAGCCTGCAC AAATACTTCTCTGCAGGGATGATCACAACCAGCAGGGGGCGCTGATGACCCAAAGGGACTTCCCAGGATC TCTTCTGGAATCTAGGGAGTTCTGGCCTGTGTCTATCAGCATGTGTTTCAATGTTAGAGTTGTGAGTTTT CCTTCCAGCAACAGAGATATTTTAGAGCCCACTTTTCATGGTCATTCTACTAAATTTGTTCACATAGTGG AAAGATTTGTTAAATGATTCTATAGTCTAATAGGGTCAAACAAAAACAAATAATTGAGTTCATATCTACC AAAAAAAAAAAAATTCCCTCAAAGTGGACAACTGTGTAGGTGAGGAAAACCAGGGGGATTTGGGAATAGA TTATTTCTCTCCCGACTGTGGTGTTAGTCACCTTTCAGCCATTTACTGTATTTAATTCATGTTTAAAGTT AATTGTATTCATCTTCCCTAACATGAAGTTTTCAAACACATGTCCACAATTTAATGATGACACAGTTATC ATTGTGAATGATAACTCATAAGATCTCTCTCCATATATGAAACACACGATATTCTGTTATTAGCTATAGC CAACAAAGTTACATATCATTATTATTACTGAAATAATTCTTCCCATCTAACTGAATAGTTTTCTCACTCG ACACTGCCTATGCTGCGATCAGCCTGCTCTAATTTTACCTTTGCTCAGAGCACTGCTTTCTGTTTCATTT GATAAGATGGTGCCTGGTTGTCACTGAAAATGTGTCCTCCAGTTTCACAGTGATTAATGTGATTTTCAGT ACATTGAGAACAGAGCCACAGCAAAAATGAGATGGAATGTCATCATTTTTACGCCAGGTGCTGCAGAAAT AGCTAGGTGGTTAAGAGAGAATATTGAACTTTGAGGGGTTCAGATTAAATTCCTGATACCCACAATGTGC ACCTCATAACCACATGTACATATAGAAAACTCAGTATAAATGTGGCCTCCGTGAGCACCACACTACTCCC ACAAACACATATACACATAATTAAAAGTAAAGATTTTAGAAAAATGGCTAATCTAATGATAGGAAGTAGT CAAAAAGAGAGTTCTTTTGTCATGTACATATGTGTAGCAGACTTAAATGTTAAACATTCAAGAATACATT CCTCGATCCACATTAAAATTTTGCAAAGAGTAGCACAGACGGTGGCAATTGCTAAACTTATATCTAGAAA CACAATTATGTGTGGTGATATTTAATTACACATTTATACCAGGACATATGACAATATGGAAACCAAACAT GTTGTATCCACATGCTCTAAGGAAAACTAAATGGAGTGTGATAAAACCAAAGAAAATGTGAATATGAAAT ATTTTTCCAACTCTGCATCTTAAAACGGTTTCTTTCATGTGTCATATCTGCTATGAGGACTTTCTTCTGC CCATGTCCAACTCCAGAGCATGCCACAGCAGGAAGACCTACAGGTATTACTTCTCTGCACCCAGGAAAAC CACCTCTGTCCTGACCCTGCAGCTCTCAGAAGAGCCCAGACCTTCATTCTCAGGCCCTCATCCAGTAATC AGCACTGAATACAGAGCACTCACCATGGACTTTGGGCTCAGCTTGGTTTTCCTTGTCCTTATTTTAAAAG GTAATTCATAGAGATAAGATTCTATCTGTTTTGTGTACATGAGAAACAGAAAAATTGTATTGTTTCTCTA TTTTGTTTTGTTTTGTTAGTGACAGTTTCTGACTCAAGATTCTCTGTTTGAAGGTACCCAGTGTGAGGTG AAGCTGGTGAAGTCTAAGGGGAGGCATAGTGCAGCCTAGAAGGTCCATGATACTCTACTGTGCAGCCTCG GATTCACTGTAAGTGACGACTGGTTTGTCCGTGTTTGCCAGGCTCCAAAGAAGGGGCTGCAGTGGGGGAT GGGAATAATTTTTCATGGTTGTGGTAGCCCCTCTTATGCAGACACCTTGAAGAAGTGGGTTGGACGTAAC ATATTCAGAATCAATATTTAAAGATTCTAATCCTTGAAGATATCACTTTTGACCAAGTATATATGAACCA TGTTACTGAGGTTTATGGAGGTTTGAGTATGTTAGGTCCATGGATAGGGAAAATATTAGGGGATTTTAGG AGTAACTGAGGCTTGTTGTAGGAAGGACATCACTGTAGGGGTAGGCTCCGTGTTCCTATCTTCAAGCTCT ACCCAGTGCAGAATAGAGCCCTCTTCTGCCGGCAAGTGGAAAGAGTTTCTCTTCCTGGCTGCCTTCAATC CAAGTTGTAGAATATCAAATCTCCTAACACTATGACTGCGAGCATGCTGACATGCGTCCCACCATAAAAA TAGACTGAACCTCTGAAGCTTTAAGCCAGCCTCTAGTAACTGTATTCTTTAATAAGACTGAACTTGGCTA TGGTGTCTTTTCACAGTAAAATGGAAACATAGACAAGGTTCTAACTCTCTGTACTAGAGGACCATCTCTA TGTCCTTGGTGTTGTATGTAAATTATTGAACAAATACTATAGACAAGTTGTATGGCCAAAAGTCCATCCC CTTCAACAATCTACTATCTGGAACCATATAGATTAGATTCCTTTCCTGCACTCATTTCCCTTACTTGCTG AGACATTTTGAAGACATGCTCAGAATCCCTGAACTTCCTGCTGAAAAAAAAATACCCCTCCAATTTGAAG ACAGTTCTCTTCCAAAATTCATCATAAATACTGATCCACATGTCCAGGCATATCATGTAGTTTTAAAAAA CAAACCAATCAATGCTAAAGTGGGTAAGTGCCTACATCATTGGTTTATGTCTGTTCATAACCTGGTATAT AGCTAGAGACCAGGACTGCATGTTTCTCCTAGGCCACACCTCTCCCACAAATGCTGGCTCTGCCTCTCCA GAATTCCAAGATCATGGATCTCTGGGTCCCCAAGGAACAATAAGTGTGCACTCTTGCCAGCCTGTACACT ACTGCACTAGCTTCTCCCCCTGGAGCTTGGTCATTGCTCAATCTTCCCTTTCCAAAGCCTGGCCAAATTC CTCCTACCTTTTGTTCTTTCAGTCAGGCCACCTAAGTCATCTTGAATGAAAAACAACACAAAATCTGAAC TTAAAATCAACAAATAATACAAGTGCTGCGCACAAAATCAATCATTCTAAACTCATCAACTATTTTATGA TGGAAATCTTCCAACATACAAGCTACCACCAGGTCTAAGAATTACTCATCTACATGTTGCTTCCTCTCAC TCACAGCCTAACCATAAAAGGGCTGTTTCTTCCTCCCATGTCCCCTCTTTTGCCTTCAGAAGCAGAAGCT CCACCTCCTCCTCTTTGCCCAGCAATTGGCTTCTTGTCGTCTTTATTATCATATTAATTACTTAGGGGAA AATCCCGTGTAGTGGCTATTCCTGGTTGTCAACTTGACAATATTTGGAATGAACTACAATCCGGAATTGG AAGGCTCACCAGTGACCCTTATCTGGAGGCTTGGAGATCCTTATCTGGATCTTGGTTTGAAGATCTTGAG CCATAGGGGCTATGGATTCCAGAAGATTGAATCTCCGAGTTTAAGGAACACACCTTTAATCTGGGCTACG CCTTTCATCTGGGATTAAAGGTGTGGCGGAACACACCTTTAATCTGGACTACACCTTCTGCTGGAGACAA TATAAGGACATTGAAAGAAGGGAGTCTAGCTCTTGCTCTTGCTCCTTCGCCTGCTTGCTGCGTGAGACTG AGTAACTGCTAGATCCTTGGACTTCCATTCACAGCTGCGACTGAACAATTGTTGGGAATTGGGCTGCCGA CTCTAAGTCATCAATAAATTCCTTTACTATCTAGAGACTATCCATAGTTCTGTGACTCTAGAGAACCCTG ACTAATACAGAAGTTGGTACCAGGAGTGGTTCTAGAGTAACAGAAGTACAAGGATGAATCTTTTAAAATA CTGGAATTGGCTTGTTGATCCACCAGCACTTTCAACTATTGAAACCTCTCCAGATTCTCTCCCTCCTGGG AGCTCAGAGAATTTTGAAGACCCATGGTTGAAACTATATTCCGAACTTAAAGAAGCAAATGCCCTTGATT TTCTTAATGAATTAGGTGATTCAGTGCACAAAGCTTTCTACAAGATGGGGAAAAAATTGGAAAATGATTT TACTGGCTGGCTGCTCTTAGTATCTGTGGAAAAAATGATGAATGAAAGGAAGGAGTTGTGTGATAAAATC GAAAGGCTCCAGACACAAGTAAACGATCTAAAAGTTGCTAAGTGTGTCCTTGAGGAGAATCTTCTCTCTT GTAGCAATAGAGCTCAAGTTGCAGAAAATCAAACAGAAACTCTCATTGTAAGGTTGGCTGAACTACAGCG AAAATTCAAGTCTCAGCCTCAGAGTGTGTCAACAGTTAAAGTAAGGGCTCTAATTGGCAAAGAATGGGAT CCTACAACATGGGACGGGGATGTGTGGGAAGACCATGTTGAAGCTGAGAATTTTGAATCTTCAGATTCTC AAGGGTTTGCCCCACCTGAGGAAGTAGTACCCTCAGCCCCACCCCTTGAAATAATGCCTTCCCCACATGA GGAAATTAATTTTGCAGAGTCTGATAAACCAGCAATGATTTTCACTACTGATGTTTCTCAAGGCCCACCA ATAGTTTCTTCTAGACCTGTAACCAGACTCAAAGCAAAACAGGCTCCTAGAGGGGAGGTAGAAAGTGTAG TCCATGAGGAAATTCGCTACACTACTAAGGAGCTTAATGAGTTTGCTAATTCATTCAAGCAGAAACCTGG TGAATATGTGTGGGAATGGATTTTAAGGGTGTGGGATAAGGGTGGAAGGAACATAAGACTAGAGCAGGCT GAGTTTATTGACATGGGTCCTCTGAGTAGAGATTCTAGGTTTAATACGGAAGCTCGCATAATTAAAAAAG GTGTCAAAAGTTTGTTTGAATGGTTGGCTGAGGTGTTTATCAAAAGATGGCCTACTGGAAATGACTTGGA GATGCCTGATATTCCGTGGCTTAGTGTTGATGAAGGGATTTTAAGACTTAGGGAAATTGCAATGCTAGAG TGGATATATTGTGTAAAGCATAATTGTCCACAATGGGAAGGTCCAGAAGATATGCCTTTCACTAGCTCTA TAAGACGCAAATTGGTGAGAGGGGCACCAGCACATTTGAAGGGTTTTGTTCTTTCCCTTTTCCTTGTACC AGATCTTAGCATTGGAGATGCTTCTGCTCAATTAGATGAATTAAATTCACTGGGTTTAGTTGGATTCCGA GGTAACAAGGGCCAGGTGGCAGCATTGAATCGCCGGAGACAAGGTGATTCTAGTTATTATAATGGACAGC GTAGACAAAAGAATGTTTATAATAACATACCCAGCAATGGTCAGCACAGGAGAGGTGAAATTTATAATGG CATGACTCGGTTGGACCTTTGGTACTGGCTAACCAATCATGGTGTTTCCAGGAATGAAATACATAGGAAG CCTACTGCATATTTGTTTGATCTGTATAAGCAGAAAAATTCTCAAACAAATGAAAGAAAGGCTACATTAG ATCATGGTAAACAGCAATCTCGGCCAGTGAATCAATTTCCAGACTTGAGACAGTTTGCAGATCCAGAACC CCTTGAATGAAGGGGTGGCCAGGTTCCGCTGAGGAAGGATCTTGATAAGACACCCAAAGGTTTTGCTGTT ACCCTTTCTCCAGTTCTTCCCCAGAGGGACCTAAGGCCTTTTACAAGGGTAACTGTACACTGGGGAAAAG GAAATAATCAGACTTTTCAGGGTCTGCTGGATACTGGTTCTGAGTTGACACTGATTCCAGGGGATCCCAA GAAACATTGTGGCCCTCCAGTTAAAGTAGAGGCTTATGGAGGGCAGGTGATTAATGGAGTTTTGACTGAT GTCCGACTCACAATAGGTCCAGTAGGTCCCCAGACACATCCTGTGGTGATTTCCCCAGTTCCAGAATGTA TAATTGGGATAGATATACTCAGAAATTGGCAGAATTCTCATATTGGTTCCCTGAACTGTAGAGTGAGGGC TATTATGGTTGGAAAGGCCAAATGGAAACCTTTAGAGTTGCCTCTGCCAAAGAAAATAGTGAATCAAAAA CAGTATCGTATTCCTGGAGGCATTGCAGAAATTACTGCCACTATCAAGGACTTGAAAGATGCAGGGGTGG TGGTTCCCACCACATCTCCGTTTAACTCTCCTATCTGGCCAGTGCAGAAAACAGATGGATCATGGAGAAT GACAGTTGATTATCGAAAACTAAATCAGGTAGTAACTCCAATTGCAGCTGCTGTACCAGATGTAGTTTCA TTACTTGAGCAAATTAACACATCTCCTGGCACCTGGTATGCGGCTATTGATCTGGCAAATGCCTTCTTCT CAGTACCTGTCCATAAGGACCACCAGAAGCAATTTGCTTTCAGTTGGCAAGGCCAACAGTATACTTTCAC AGTTTTGCCTCAAGGATATATTAACTCTCCTGCCCTGTGTCATAATTTAGTTAGAAGGGATCTTGATCGT TTGGATCTTCCACAAAATATCACATTGGTGCACTATATTGATGACATTATGCTGATTGGACCAAGTGAGC AGGAAGTAGCAACCACTTTGGACTCATTGGTAACACATATGCGTATCAGAGGATGGGAAATAAATCCAAC CAAAATTCAAGGACCATCTACCTCAGTGAAATTCTTAGGAGTCCAGTGGTGTGGAGCATGCAGAGATATT CCTTCTAAGGTGAAAGATAAGTTATTGCACCTGGCCCCTCCTACAACCAAGAAAGAAGCACAACGTTTAG TGGGTCTATTTGGATTCTGGAGACAACACATCCCTCACTTGGGTGTGTTACTTAGGCCTATTTACCAAGT GACTCGGAAAGCTGCTAGCTTTGTGTGGGGCCTGGAACAGGAGAAGGCCCTTCAACAGGTCCAGGCTGCT GTGCAGGCTGCACTACCACTTGGACCATATGACCCAGCAGACCCGATGGTACTTGAGGTGTCTGTGGCTG ATAGAGATGCTGTTTGGAGCCTCTGGCAGGCCCCTGTAGGTGAATCACAGAAAAGACCTTTGGGATTTTG GAGCAAAGCTCTACCATCATCTGCAGACAACTATTCTCCCTTTGAAAAACAGCTCTTGGCCTGCTATTGG GCCTTAGTGGAAACTGAACGTTTGACAATAGGACACCAAGTTACTATGCGACCTGAACTACCCATCATGA GCTGGGTACTATCAGACCCTGCAAGTCATAAAGTGGGACGCGCACAGCAGCAGTCTGTTATCAAATGGAA GTGGTATATACGTGATCGGGCCAGAGCAGGTCCTGAAGGCACAAGCAAGTTACATGAAGAAGTTGCTCAA ATGCCTATGGTTTCTACTCCTGTTACACTGCCATCTGCTGCCAAACATGTGCCTATAGCCTCATGGGGTG TTCCCTATGATCGACTGACCGAAGAGGAAAAGACTAGAGCCTGGTTTACTGATGGCTCTGCACGTTATGC AGGCACCACCCAGAAGTGGACAGACAGCTGCAGCATTACAACCCCTTTCTGGGACAACCCTGAAAGACAC AGGTGAAGGGAAATCTTCACAGTGGGCAGAACTTCGGGCAGTACACATGGTATTACAGTTTGTTTGCAAG AAGAAATGGCCAGATGTACGATTATTCACTGACTCATGGGCTGTAGCCAATGGATTGGCTGGATGGTCAG GGACTTGGAAAGATCACAATTGGAAAATTGGTGAGAAAGACATCTGGGGAAGAAGTATGTGGATAGATCT CTCCAAATGGGCAAAGGATGTGAAGATATTTGTGTCCCATGTAAATGCTCACCAAAAGGTGACTTCAGCT GAGGAGGAGTTCAATAATCAAGTGGATAAGATGACCCGTTCTGTGGACAGTCAGCCTCTCTCCCCAGCCA TCCCTGTCATTGCTCAATGGGCACATGAACAAAGTGGCCATGGTGGTCGAGATGGAGGTTATGCTTGGGC TCAGCAACACGGGCTTCCACTCACCAAGGCTGACCTGGCTACAGCTGCTGCTGATTGCCAGATCTGCCAA CAGCAGAAACCAACACTGAGTCCCAGATATGGCACCATTCCTCGAGGTGACCAGCCAGCAACCTGGTGGC AGGTTGACTACATTGGACCACTTCCTTCGTGGAAAGGACAGCGTTTTGTTCTTACTGGAGTAGATACTTA TTCTGGTTATGGATTTGCCTTTCCTGTACGTAATGCCTCTGCTAAAACCACCATTAACGGACTGACAGAA TGCCTTATCTATCGTCATGGTATTCCACACAGTATTGCTTCTGACCAAGGAACTCATTTCACAGCCAGAG AAGTACGACAGTGGGCCCACGATCATGGAATTCACTGGTCTTACCACATTCCCCATCATCCTGAAGCAGC TGGTCTGATAGAAAGATGGAATGGCCTTCTGAAGACGCAGTTACAGCGCCAATTAGGTGGTAACAGCTTG GAAGGCTGGGGTAGAGTTCTTCAGAAGGCAGTATATGCTTTGAATCAGCGCTCGATATATAGTACAGTTT CACCCATAGCCAGGATTCATGGGTCCAGGAATCAAGGGGTGGAAAAAGGAATAGTTCCACTTACTATCAC TCCTAGTGACCCTCTAGGAAAATTTTTGCTTCCTGTCCCCATAACTCTAGGTTCTGCTGGCTTAGAAGTT TTGGCTCCAGAGAGGGGAGTGCTCCTACCAGGAGCTACAACAAACATTCCATTGAACTGGAAGCTCAGAC TTCCCCCTGGTCATTTTGGGCTTCTAATGCCCTTAAACCAACAGGCTAAAAAAGGAGTAACAGTGTTAGG AGGGGTGATAGATCCAGATTACCATGGGGAAATTGGATTACCTCTTCACAATGGTGGTAAGCAAGATTAT GTCTGGAGTGTAGGAGATCCCTTAGGGCGTCTCTTAGTACTACCATGTCCTGTGATTAAAGTCAATGGGA AACTACAACAGCCTAATCCAAGCAGGATGACAAAGGACACAGACCCATCAGGAATGAAGGTATGGGTCAA TCCTCCAGGAAAAGAGCCAAGACCTGCTGAGGTGCTGACTGAAGGAGAAGGAAATATAGAATGGGTAGTA GAGGAAGGTAGTTATAAATACCAATTAAGGCCACGTAACCAGTTGCAGAAACGAGGATTATAAAGTAATA TGAATGCCCATTGTAAATTTACTAATGCGTTTGCGATTGTACGAGGGATAGTTATATCATGTTAGGCGTA TTTACAAACTTGTTATTGTTTTATGTGAACATGAGATATTATTTGTGTCAAGTTGACAAGGGGTGGATTG TAGTGGCTATTCCTGGTTGTCAACTTGACAATATTTGGAATGAACTACAATCCGGAATTGGAAGGCTCAC CAGTGACCCTTATCTGGAGGCTTGGAGATCCTTATCTGGATCTTGGTTTGAAGATCTTGAGCCATAGTGG CTATGGATTCCAGAAGATTGAATCTCCGAGTTTAAGGAACACACCTTTAATCTGGGCTACGCCTTTCATC TGGGATTAAAGGTGTGGCGGAACACACCTTTAATCTGGACTACACCTTCTGCTGGAGACAATATAAGGAC ATTGAAAGAAGGGAGTCTAGCTCTTGCTCTTGCTCCTTCGCCTGCTTGCTGCGTGAGACTGAGTAACTAC TAGATCCTTGGACTTCCATTCACAGCTGCGACTGAACAATTGTTGGGAATTGGGCTGCCGACTCTAAGTC ATCAATAAATTCCTTTACTATCTAGAGACTATCCATAGTTCTGTGACTCTAGAGAACCCTGACTAATACA TCCCTACATACAGGAAACTTGATGTATAAGTAAAGAAAATAGTAAATCTAAAAATTTCCTTATCAAATAC ATGCAAGAAATCCAAAATACCATGAAAAGACCTGATCTAAAAATAGTAGGAACTGAAGGTGAAGTGTCCC AGCTCTGAAAACTAGAAAATGTTTTCAATATTTTTCCTAACAGTGAAGACATGGATCTAATGAGGCCACC TCTTATAGCCATGCAAGACTGACAGTGGAGGGATAAGGACACCAATCCACCCACAAAACTTTTGACCCTA AATCAGTTTTATCTAAAAGCAATGCAGGGGCACAAATGGAGCAGAGACTGGAGGAATGGTCAAACAATAA CCTGTCATATCTGAGACCCACCTAATTGGCATACACCAGTCACTGACATTATTAATAATGTTCCATTATG CTTACAGGCATTTCTCTAGCATTACTATTCTTGGAGAGACTTCACACAGCATCTTATTGAAACAGATGCA GACACCCAGAACCAAACATTGGATGGAGATTGGGATCCTTAAAGAAGAGTTGGGAGGATAATTGAGAGAC CTCAAAGGAATAGCAACCCCATAGAAAGACACGAACAGGGTCAGTAAACCTGGACCCATGGGGTATCTCA GAGACTGATCACCAACCAAAAATCACAGAGGGCCTGGATTGATTCCCCTGGCACACATGTAGCAGAGGTC TGCCTTGTCCTTCAGTAGGTGAAGATGAGCCTAAGGCTTCAGAGACTTGATATATCAGCATACAGCAACA CCCAAGTGTGTCCCACTATCTCAGAGGTGAAGGGGTGGAGATGGGCAGAAGGGTCCTGATAGGGGACAAC TGCAAAGAGGCAATATTTGGGACAGAAAGAAAGGAAGAGAGAGGAAGATAAAGAGAGAGATGAAGGAAGG AAACAAACAAACCAAGATGAAGAGAGAGAAAAGGGGGAAAATAGCCTTGAATGGTTCAGGGATTCAAAGG GACATACCTAAGCATGGTAAAACAATGCACATAATGGCAGCAAGTAGCTAACACTGAATTAAATAGAAAG ACACATAAAGCAGTTCTACTAAAGTAAGAGACAGAGTTGCCCAATCTCACCCTATTTATTCAATAATAAT GTACTTGAAGTTCTAGCTAGGGCTGTAAGACAACTCAAGGAGATCGGAGGATACAAATTAGAAAGAAAAA TTCAAAGAATTGTAATTGGTAGATGATAGGATAATATACATAAATGACCTCAAAATTCTTCCAGAGAACT CTGAAAGCTGATAAATACCTTCAGCAAAGTGGCTAGAAACAAAATTACTTCATAGAATTCAGGAGCTATC CTTTATAGAAAAGTTAAAGTGGCTGAGAAAGAAATTAGGAAAATCACATTCTTTGCAATAACCAAAAATA ATATGAATTAGCTTGGTGTGACTCTAATCTTGCAAGTGAAAGATGTGTGTGACAAGAGCTTCAGGACCCT GAAGAAAGAAATCAAAGAACTCAAAGATGCAAAGTACTCTAATGCTCATGGATAGGCAGAATTAACATAA TGAAAATGCCAAATTTAACAATTCAATCTACAGATTCAGTGGAATTCCCATTAAATATCCAACCCAATTT ATTACATTCTTGAAAAAGCAAATCTCAACTTCATATAGAAAAACAAGAAATTGAGGGTAGCTAACAAAAT CCTGAACAATGAAAACACTTCAGGAGAATTCACCATCCCCTACCTCAAGCTGTATTTTAGAGCAATAGTT ATTAAAACTGCATGGTATTTGTATAGAAACAGATATGATGATCAATGTAATTGAATTGAATACACTGACA TAAAACCACACTGTTATGGACACTTGATTTTTGACAAAGAACCCAATAATCATAATAAAAATCATAATAA GAATGCATCCCCCAACAAATGGTCCTGATCTAAATGCAAATAGATTCATATCTATCATCCTGCACGAAAT TCAAATCAAAGTGAATTGCAGACTTCGACCTAATACTGGATTAACTAAATCTAAATGAACAAAAAGTAGA GAATAGTTTTGAACTCATTGATGCAGGATTCAATTTCCTGAACAGAACCACAATGGCTCAGGCTCTAGGA TCATAAATTGGTAGATAGGATCTCATGAAACTGAAAAACTTCTGTAAGGCAAAGGCAATAAAACAAAATG GCAACCTACAGATTGGAAAAAAAATAATCTTCAGTATCCCTAAATCCCATTGAAGGCCAATATGCAAAGT ATATAAAGAACTCAAGATGTTATCCTCCACAAAACCAAATAAATCAATTAAAAATGAACTACAGAGCTAA CAAGAGAATTCTCAACAGAGGAATCACCAATGACTGAGAATCACTTAAAGAAACATTCAATATTTGTAGT CACCAGAGAATTGCAAATCAAAACTACCCTGAGATTCTACTTTATACCAATCATAATGGTCAAGATAAAA ATTCAAATGACAGCGCATGTTGGTGAGGATGTGTATACTTTTGCATTGCTGGTGAGGAAAACAATCTGGC AGCTCCTCAGAAAATTGTAAATAATTCTACCTGAAGATCCAGCCATACCACTCCTGTGCATATACATAAA ATGTGCTCCACCATACCACTAGGAGATATGTGCCACTATGCCCATAGCAGCCTTATTTGTTAATAGCCAA AAGATGGATACAACCCTGATGTGCCTCAAACAAAGATTGTATATAGAAAATATGGGTTCCCTTACACAAT GGTATTCTACTCAGCAATTAAAACGTGAGAACATCATAAAGTTTTCAGGCAAACTGATCAAATGAAAAAG TATAATCTTGAGTGAGGTAACAGAACCAAAATGACCTGCATGGGATGTACTCACTGGTAAGTGAATATTA GACTAAAAGTATAGAATATCAATGATGAAAGCCACAGACCATAAAGAGTTTAATAAGATGGAAAGCTCAA GTACGGATTCTTCAATCCAATATAGAAAGAGGGACAAAATAATCAGGGGAGGCAGAGGGAGAGAGAGACA TTTGGTGGAAATGGGAGAAGAAGGGAGAAAGGCAGAAAGGATCAGGCGTTGGGGAACACTGGAAAGCAGC CCAGGGGTCCTGGTAAATGGATTAAATATTCAGCTGAATGGAGGTGGGAGGCAGGGGGAAGCTCTGCAAA GTCCAAGAGACCTGGGATGTGAGAGGCTCCCCAGATGATAATCTTAGCCTTCATGCCTAACAGTTGTAGA TAAACCCTGAAGAGATCACTTCCAATAGATGCAGAGGGCCCTAAGTGGTTGGATGGAGTCCCCCAACTTA CCTCAAAATTGTCAATACTCATAGAAATTAGGACAATGAAAATCAAAACACCCTGAGATTGTATCTTATG TCTGTCACAATGGTTAAGACCAAAACCTCAAGTGATGGCTTGTGCTGGCAAAGATTCAGAATAGTAAAAG TCTCCCCATGGCTTGTGGGAATGCAAACTCTTACAACCTCTTTGGAAGTATATTTGATTGTTACCTGGTA TAAAATGGCAAAAAAAAAAAATGGTTGAAGGGGGACTAAAAAAGGAAGAAAGGGGAGAACTATGGGATGC GAAACAAGAAAGTTTGTTGCAAAAGAAATATGTTTCCACTGCAAACCCTGAGTCTCAGACAGAAGGGGAC CTGGAATTCTTCAGATACAAAGAATCTCTAAACCCTGAGGACATTCTATCACAAATAAGTAAAATTCAGA AAATTCTGAGTGCTCCCATCACGGAGATGAATCTGCTATGAACAGCTCATAGGTGTGACCCTCTACAAAA GCCATATTATTGAAAAGCCACATTGTGCCCAGACTTTGGAAAGACTGAGCTCATATCCTGAAATACAGTT ATGTGTGGTTCTATTTAATTACACATTTACACTAAGAAAACATGGCAGTATGGGAATGAAGCTTGTTCTG TACACATTAACAGAGGGAAACTAAACAAAGTATGGTGAATCCCTAACCAAAAGTAAAAAAAAAAAAAGAA AGAAAAGAAAATAAAAGTGAAACTACAATATGTTTCAAATGCTGTAACTGAAATCTGGTTTTTTGATGCT TATATCTGGTATCATCAGTGACTTCAGATTTAGTCCAACTCCAGAGCATGGTATAGCAGAAAGACATGCA AATAAGCCTTCTCTCTGCCCATGAAAAACACCTCGGCCCTGACCCTGCAGCTCTGACAGAGGAGGCCAGT CCTGGATTCGATTCCCAGTTCCTCACATTCAGTGATCAGCACTGAACACGGACCCCTCACCATGAACTTG GGGCTCAGCTTGATTTTCCTTGTCCTTGTTTTAAAAGGTAATTTATTGAGAAGAGATGACATCTGTTGTA TGCTCATGAGACAGAAAAATTGTTTGTTTTGTTAGTGACAGTTTTCCAACCAGTATTCTCTGTTTGCAGG TGTCCAGTGTGAAGTGAAGCTGGTGGAGTCTGGGGGAGGCTTAGTGCAGCCTGGAGGGTCCCTGAAACTC TCCTGTGCAACCTCTGGATTCACTTTCAGTGACTATTACATGTATTGGGTTCGCCAGACTCCAGAGAAGA GGCTGGAGTGGGTCGCATACATTAGTAATGGTGGTGGTAGCACCTATTATCCAGACACTGTAAAGGGCCG ATTCACCATCTCCAGAGACAATGCCAAGAACACCCTGTACCTGCAAATGAGCCGTCTGAAGTCTGAGGAC ACAGCCATGTATTACTGTGCAAGACACACAATGAGGAAATGTTACTGTGAGCTCAAACTAAAACCTCCTG CAGAGCACCCAGGACCAGCAGGGGGCGCAGAGAGCACATGGAGTTCTGATTCACAGAAGAGTTACAGCCT GTACAATTAGACCCAATCTTCAACAAACCGTCAAAATATTCGATCCAAAATTGTTCCTGTCTAAAAGTAA TTCAAGGACAAAATGGACCAGAGACTGAAGAAATGGCTGACCTGTGACCCTCCCAACTTTGGATCTATCT CATAGGCAGGTACCAAACCTTGACATTTGTCACTGACACTGTATTGTGCTTGCAGACAGGAGCATAGCAT GGCTGACCTCTAAGAGGCTCTGCAAGCACCTGAATGAGACAGATGTAAATAGAGTGTACAACTGGATTAA GTTTGAAGACTGCAATGGAAGAGTTAGAGGAAGGAATGAAAAATCTGAAGGGGATCACAACCCCAGAAGA AGACCAACAGTGCCAATTAAACTGGATGCCTGGGAACTCCCAGAGACTAAGCCACAAACCAAGAATCATG CAGGCTGGTCTGAGAATCCTGGCACCCAAGTCTCAAGGAACTGCCTTTTCTTGGCTCAGATGGGAGAAGA TGAGCCTAAAGCTTTAGACTTGACGCCCCAGGGATGGGCAATACAAAGTTGAGTTTCTTGGGAAAGTGAA GAGGATGGTGGGAGGAGGAATAAATCTGGGAAGTGGGACTGGTTGGGGACAACATATTGGTCCTAAATTT ATGAAATAATTATCTAATTGATAAAAAGAGTCCTTGGGGTAATGGAGGGCTAGACTCCTCTGTGCCTAGT TTGTAACTCTACAGGGATCCTCTTTAAAAGAATAGGGTGCACATAGAGTATATGTGTGTGACACTAATAC AGGGGTAAGTGTTTCTGTAAGAACTTTATGAATAAACTTTATTAAAACATCAAAAAGTATAGGTTGTAGC AACCCTTGACCTGTACGAATGTTTATAAAACTTTCTATTTTCCTTAATTATATCTGTTTTGCATTTGTTT ATTTATTTATTTACTTACTTACTTATTTATGATTTCACTGTGTCTTTCTGTAGTCCTGTATGTGTTTATT TGTCTCTTTATTGCTCTGTTTCTGTTTCTTTCTCTCTGTCTAGTATTGTATCTCTCTGTGTCTCTATGTC GCCGATTGTGTCTGTGTGTATGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGCATATTGAAA TGAGATCTCTTCTTCTATCAGTGTACATAATGACTTTGAAATAAAGTCCATCACTGGGCTTGGATATCAC TATCTTGTTAGAATGGTTGCCCAAAGTGTTCCAACCATCACACTGTTTCTACATATAATAGATGGGTTTA TTGATTTACTACCAAAACTACCCCATCTTAAGTTATGGATATTAAACACAGATCCTCATGGTGTGTTAAG AACTTGAAGCACAGAGCTATATGTACAGCCCACTAAAAATGACTTAAATATAAGATAAACTCTGGCTTGA ACAAAACACAGAGCATCACACGAGGCAGAAGTGAATCTCTATGAGGACCAGGATCACATCCCAAAGAACC AAAGAACACTTGAGACTGTGGAACCCTAGAGTCAGGGCTGACACTCAGTAAGATTTACTTCATAGAGCAT GATGTGGGATTCAAGAAGAAATCAGGCAGGGCCTGTGACCCATGAACCAGATGACTTCCAGTCTCTCCAT CATCCTCACACAAACCATAGGCAACAGCTCAGCACTGACTCACCTGTGATGCTGGTGACAAAATGTGTGC AAAGCCTCAGAACTGAGACGTGAGGCCAATGTTGCTACCGACACTCAGTGAGCTTCAATTTGCTGCAAAC TGCTCCAAAACAACTCAAAGGGTAACTTCTTCTTTTTCTATTTGTACTTGTGATGCCTTGGTAGATATAG TTCCCCAATAATTTAATAGGACAAATCATTTTTCCTTTTAACACATTAATCCCCTTTCCTTCCCCCAAGA TTCTAAAATTTTTCTTTAACACTGATGTCTGAGAGATATGGCATAATAGATGTTTGTCTTATTCTGAGTT GTTCCTTATCAAAAGAAATCAGCTGTGGCACTTTGAACCTAAATATAACAATATTTCACAAAGGCATTCT GGGAATATATAGATGGTATTGCTACAAAAGAATAGGAGGATCTATGGCCATACCACCCTTAATGAACCAG ATACTATCTAAAAGATTAGGACAGCTGGGCATGTTGGCACAGGCCTTTAATCCCAGCACTAAGGAGGCAG AGGCAGGCAGATTTCTGATTCGAGGCCAGACTGGACTACAAAGTGAGTTCCAAGACAACCAGGGCTATAC AGAGAAACCCTGTCTCGAAAAAACAAAACAAAACAAAACAAGAGTAGGAGGGTATTAGATGCGAGGTGAT GATGGCCATTCAATCAAACCAGAATGTGACCTGAGAAAAGGTCTAAGTTTGTCAGCTTGTCCTGGAGATG TGTTGCCTCTGATAAATGCAGAGCTGGAACTGCAATACATTGGATTCCTGTGAGTTACGGAGAAATAAAA GGAATAGCCTCTGTTTCCTTTGGTTCATCAAGTTGGCAGTGAGCTAGAAGATGATACTGGGAACCATCAC ATGTACTTCTACAGAGTTATTCTACATTCTACAAGTCAGTCTTGCTTGCTTTCGTTTCTGTGAGGAGCTA AATACAGAATGTTTTCAATGTCTCATAATGTTCTGTGCACACCCATGGGTGCCTAGCCAAGGATAGAAAC TTGTATCTGATAAGGAAAGAGGATGCTGCAGTGGCCACACTCTGAGATCACCTCCTGCCAAATTATACTA GAGTGTTTTACATAGTCTTGAAAACACTAGGTCAAATATGTTGTCATCCAGATATGAAAACTCTGTGCAA CAATTCAGAAATACAGTGGTCAGGACAACTGGTATGTAACACTTTAGTTCCAGCCCACATTAATCTCACA TCTTTTCTGTGGTTTCAATAAAGAGCACACATGTTTGGAACACCATCTCCACTTTGTATGCTTATCCTTA TGCATCAAACTTTTCCTGTAATTTCCTACCCCGCACAGGTTCCTGTCTTGATCTCTTTTTCTAATGAACA GCAATACAGAAGTGTTGGCCAAATGAACACTTTCACCCCAAGTTGCTTTGCCATTGTGTTTCATCACAGC ATTAGTAACTCCCAGTAAGGCTACTGGTTACCCTGCATCTTCTATGTAGATCTTTTGATGAAGTTCCAGG CTTGGGGTCTTTATCTGACTGTTATCCTGGTTAATTCATGTCCACCAATAGAATATTGTTCTCATTTTCA ATATCATATGAAGTTACCTGTTTATAGGATCTTCCTAAAGCAGAAAACTATATAAAATGTCTGCTTACTT TAAGAAAAGTATGTGTCCTTGGAGGTAAATGGAGGAAAGGGTGGAGGATGTTGAGTAATGGAAGACTGGC TAATACAGGAAGGTCACAGAATTGAATGATTTTAAAAATTTTAACTCCTCATCAATGAGGTACTTCAAGT TGAGGCAGGAGTCCTTGATGCACAGGTGACCCAAAGGCCCCAGCCTCTGTTTCTTGGTCTGCTCCAGTCT CCCGGCTCAGCACAGTTCACTGAGTGACAATCTTTAAGATAGTCTTTCAGGATACAGTTATCACAGTTTT CAAACTCTCTTCATTGAAACAATATAATGAGTCAGAGTCCAGTGTGCCATTAATAGGCCCTATGCAATAG GATTTTACTTCATCTGTGGAAAGAAACCACCATGGCCTCATCAAGGCCTCATTTGATGATTAGTGTAGAA AGCGTCCCCAGAGCTTTGCTGGGATGAAAACCCTGGCAAGATGTTTAGGGCACTCTCCATCTGACAGGAC AATTCTATCAAGGGTTGCTTCCATATAGAGAGAAATCTCCACATCTGCAGTATTTCCCGATTTATCAACA GTTCTTTACCCCGTGTCATATGCATAAAATCTTTTCTCTGTAGAATTTTCAGTACTAAAAACTAACAAGG ATGTTGGTCCTGATATCAGACATAATAAATAAATAAACATCAAATTATACCCTAAACATGTGGAGATGGT TTTCTGTTATGAATTTATTGGCTCTCTAAAAAGTGTTAATTAAGCCAGGCGTGATGGCACATGCCTTTAA TCCCAGCACTTGTGAGGCAGAGGCAGGCGAATTTCTGAGTTTGAGGCCAAACTGATCTACAGAGTGATTT CCAGGACAGCCAGGGTTACACAAAAAAACCCTGTCTCCAAAAAGTAACAAAAAGAAAGTGTTAATTAACA TCTACACTTTAAGATAATTTGGTGGCAAAGGTTAATAGTCTGAAATACTAGATATGAAAGTATGACACCT AAATTGCATGCAGAGAATAAAGCTGAATTCCAATGAGATTCATGCCTTGTGAATCCATTCCAATCTGATC TCAATCTTCAAACATGTTTGTGCATAATTTACATCTTAATCAGTTGCTGGAAATTAAAAGGACATAAGCT AAACTTAAAACTCTTTCTATTTAATGTGTCAGAATAGAATATGTGCACTGAAGTTTTCATGTGCATAGGA TATCATTGTTACAATGATGGTTCAAATACGCACCAGTAGCACAGGTGATGCTTGACATGAAAAAAACTGT GACCAGAGCCCAGACGTTGATGTTGGCTGAAAGAGCCTAGTGTCTCACATTTGATCAAGCAAAGTGTTAT TCAGAGAAGCAGTGCCAGATTTGGGATCCTTCTTAATGGATCAAGAACATGAGGAAGATTTGGAAGCCAG ATTGATGAGATTACTAGAATCCTGGATCTGAACACACAACACACAATAGTAAGTTGAACTTTTCCACGCA ATGCTAAAGATAAAGCATCCAGTATCATGTTATACAGGACCAAGGTGAGGATCAGTCTGTGGGTGAAGTA CAATGAACTGGAAATTGTTTGGATTTTAAATGTTGGTTTTTAAATTATATATAAAATATATATATATATA TATATATATACATATATATATATATATATATATATATATATATATCGGAACCAACATTTAAAATTTGGAT TTTAAATGTTGGTTTTTAAATTATATATAAATTATATATATATATATATATATATATATATATATATATA TATATATATATATATCGGAACCAACATTTAAATTCCTAATTCTTAAGGACTTCACTTTTGACCAAAAATA TTTGAAATGGGTTATTTAGGTCTGTGGTGGTTTGAATATGCATAGCCTATAGGAAGTGGAAGTATGGCCA TTTTGTAGTATGTGTAGCCTTGATGGAGGAAGTACATCACTATATGGTGTTGTGAGAGTTGAGATCCTAT GTTCAAGTTCTGCCAAAAACAGAAGAGAGTCCCCTCCTGGATATTTGAAACAGATGCAGAGGCCCAAAGC CAAACATTGGGTATATCTCAGGGTTTCTTATGGAAAAGTTGGCTGAAGGATTGAAGGCCTTAAAGGGGAT AGGAACTTCACAGGAAAACCAACAGATTCATCTAACCTAGACTCTAGGGGTCTTTCAAAGGTTGAGTCAC CATACAAAAAGGACACAATGGCTAGACCTAGGTCCCTGATACATATGTAGCAAATGTGCAGCTTAGACTC CATGTGGATTCCCCAACGACTAGAGCAGGTATTGTCCCTGAAGTTATTGCTTGTCTGTAGAATACATTTC CCAACATAATTGTCTTGTCTGGCCTCAGTAGGAGAGTATGTTCCAATCCTGGAGAGACTTGATATGCCAG GATTGAGAGATTAAGGGTCTCCCACCATCTCAAAGTTCATGGGTATGACAGGGGAGGGGCAGTGCAGGTT TTCCCCATCTCTGATTTCCAGCATTTGCACCCCCAATATTGAGGGGGAGGTCTAGCAATTGGAGGGGGGA CAAACAGTATGAGAAAGCTAACTTTAGTGGTGTTGTCACAGTGTGGGGTATTGTGGGTGGGAGTGGAGAT GAATCCTCCTCCTCCTCAGGAGGCTGTAGCAGGTGCTTGCCCTCTTTTGGGACAGTAGAGCTGTGGTCAG TACTGGCCTGTTCCTGACAAATTTATTCTGTGCTGTGACCATTTATTCAAGGGAGGAAGATTTAAGACTT GCTATGATAACCTGACGAATCTGGACAAACAAGAGACAGGAGGTAACACCTGAGTTACTCTTTTGCTTGC TAGTACAGAAGAGCACTATAATCCACAAATTGGGGTCCCACATATTCTTGAGTGGGATCCAAGGTGCCAT AATTTCAGCCACATTCCAAAGTCCCTCAAGGTCTGACAGTTTAGTCTTTAGGCTTCTCCTAACCAAATCA TATTTGGAGTTCTTTAACATAAAAGGGTAGTTTCCCCATATCACTGCCAGCAAAACAGGTTGAATTTGGA CAGACAAGCAAAACTATCACAAACAAGACAGACTATGTGTGCGATCCAAATGTCTTGTGATTAGAGGGGA AGTTCTGCAGCTTATTAGGCTGTGTCCTTATGCCCACAAATGTCTTCAGATAGGAAAGGGCCATTGGGTG CCAATCCTTAGTTCTTCTGTTTCCTGGGCTGTCAGTTTTTATGTGGAGAAGACATGAACCAAATGCAAAG TCATGTATCCTACAAGAACTGACATACACAGACAAACAAGGAATAACAATGAGCTCTCTCATTCACCTAA GGGGGTCTTATAACATAGAACAGAAAGGGGCCAACTTAGCAAGAATTGACCAAAAGGTGGTCACCTAGAC CACACCACAATGCAGGAAGGATATCAATGAAGGAAGAACAAAGGAAAGGCCAAATCAAGTTTGTTGGCAC ATGACATAAAACAGTGCTCAAAAAACAATAGATGCGAGCAAAATGAAGCATTGGAATCATATCGGGGTAC ATAGGGGTCACTCTTACCCCTGTTCAAGTGCCAGATGTTGTTTTAGCCTTAGGCTCCCTGAGTTTGTCTT TAGGGGAAATGGGTAAGAATACACAAAAATAATGTCACAGAATCTTAGAGGCAGATGAGAAGTCAAAGCA GACTCATTTATTGCTATAGAAAAGAATGCCTTTATACCTTCTGTCCATAACACCTCTGCCCATATATGCT CATCTCTGTGAGGCAATGGACTACCTGCAGACAGGCTGGTATCCAGTCAAGCTGAGGTCTGAACCACAAT GGTCGTAACTCACCTAAAGGACGTGGTAGGCATGACGCGATAGGCGTTCCCTCATGCTCCTGGAACTCCG GCCCCTGCCTAAGGTACCACCTCCCACAGCCCCCACAAGAGAAGCATGGTCAGTAGTCATGTAAGCAATG GCCCAAGCTTCTGACCTTCAGCCTAAACTCCTCCCCAGTTACCTAGCAACAGTGAAGACCATAAAATGGG ATGTTAGGCCCCCACCTCACTCTCTTACTCCTTTGTTCCTTTACCTCTCACTTCTCTCAATTCTCTCTCC TCTTCCCTTTCTTTGTCTTCTTCTTTCCTTGTCTCTCTGTCTTTCTCTTTCTCTCTAGCCTTCTCTGCCT CTCTCTCTCTCTCTGTCTCTCTGTCTCTCTCTTCTCTCTTTCCCTTGAATTTCTTTTTTTCTTTTTTCTT TTTTTGATGAGCACAGTATAAATAGTTTATTGCATTGTTTCTGAATGTGGCTGTATTCTCTATTGTTCTC TTTCTTATTTTTTTTCTTTTTTTGGTTGTTTTTGTTTTTATAGTCTCGCACAGAATTCTACATCTACCAA ATCCCCATTGTGTACTTTAGTTTTGTCTTGTATTCAAAGGTTCTTTCAGAAAGAATCTTAAAGATGAAAT TTGCCTTCCAACTTTTCAAAAATACATATAAAGATAGATGTTACATAGTTCACGGAATAGACACATATAC GGAGATGCAGCAATATCTCCTTTGTGCCTCTTGTATATTCATGTTATTTCCTCAACTAAAAATACATAGC CACAAAGACATACAATGAGCACTCCACTTAGGAAAATATGGCCATATTTTTTTACATTTTTATGATTTTA TGATTAGGTATATTCTTCATTTACATTTCCAATGCTACCCCAAAAGTCCCCCAACCCTTCCCTCACTCCC CTTCCCCACTCCCACTTGTTGGCCCTGGAGTTCCCCTGTACTGAGGCATATAAAGTTTGCAAGACCAATG GGCCTCTCTTTCCACTGATGGCCCACAAGGTCATCTTCTGATACATATGCAGCTAGATACATATACATAC ACGAGCTCCAGGGGGTACTGGTTAGTTCATATTGTTGTTCCACCTATAGGGTTGCAGATCCCTTCAGCTC CTTGGGTACTTTCTCTAGCTCCTCCATTGAGGGCCCTGTGATCCATCCAATAGCTGACTGTGAGCATCCA CTTCTGTGTTTGCTAGGCCCCATTATAGCCTTGCAAGACAGCTATATCAGGGTCCTTTCAGCAAAATCTT GCTAGTGTGTGCAATGGTGTCAGCATTTGGGGGCTGATTATGGCATGGATCCCCGGATATGGCAGTCTCT AGATGGTCCATCCTTTCATCTCAGCTCCAATCTTTGTCTCTGTAACTCTTTCCATGGGTGTTTTGTTCCC AATTCTAAGAAGGAGCAAAGTGTCCACACATTTGTATTCATTACTCTTGAGTTTCATGTGTTTCCCTTGC ATTTCTATAATAAACCATAAGGAGTCTCTGCTCTACCAAGACCCGCTGCACACTCTGGTCAGTGTTGGGA ACTTTTCCCCTATTCCCTCTCTCCTATAACTCCGGGGCTACAGGGTGTCTCCTTTGGGTCCCGGTTGGGA GCTGTCTCTTCTCAACCCCCTGACTCATGGGTCAGAGGCCTAAATCTCCACCCAAGGCTGTGTGAAAAGC ACCGGGTGGTCTCCCCATATCTCCCTGTCCAGAGCACAGGAACTCTGGCCGGACATGGCATATTTTTCCT CCCCAACTTCTTCCCCGGCCTCCTCAGGGCTGTCCCTTCATTTTGTTCCCCACACATCTCCACATGGCTG CCACCATCCAATTGGCTGCTGAGGTCACACACTCTGTCTTTGTTCTTCTCTGAGTCTCATGCAGGTTTTG TGTTAGTAAATGCAAAAGTGCCTGCTGTGCATGCATGAACCATTACAGGCTGCTAGGCAGAACATGCTGA CTTGCTCCTGGATTATAAATCCATCACTGTGATAGCAGGACATATCCAGAAGACATTATTTAACAACACT CCTCTTCGTGCTCAACCTCTCATGGTCTTTCTACCTCCTCTTTCTTAGTGTTCTCTGAGCCTACATGAAA TGTGAACAAACCTGAAAAAAATCTCTGTGTCAAATACATAGTGTGGATTGGGAAGGAAAAACCCTGCACT TGTGTGTGGGCAGGGAAATGCTGGTGCTTTAACAGGACAAGTGCGGTGTGGCTAGAGAAAGTGATGAGAA GAAGGGAAGCATGAGAACTGGGTGGGTGGATCCCATGTCTACTGAAAATGCTATGTTGATGTCAAGATAT TGTGTCTTGTTACAAAAATTCATTGAGTACCTAGGTTATTCTCAGTATATAAAAGGGGAGGAATGAAACT AGAATTAAACACACACACACACACACACACACACACACACAAACACACACACACGAGTAGAGAAAAGAAA TAGTCATGAGTTGCCTAGTGAATGAAGAGCGGAAAATGGTGCAGTTAATAGGGATCATAGAAAGAACTGG GGGATGCACACGAATGGGTTTCCTGTAATTATGTCTTCATAGTAATCTCTGCTCAATAATCAGACAGTGA CAATGTATGCCTCATTTACAAGCCCTGATGGCCTCTCAGAGGAAAGCATCTCTCTGAAATGAATAAAGTT CAGAAATGTCCTAAGTGTCCCTGTCACAGGAAAGCAGTGTTGGTAACGTTTCCAGGAAGCTCAGTCTTTG TCAAATATCCACAACAAGAAGAAGCCATGTCTAGACAGACAACAGACTGGGAAAGACTGAGCTCATGTAT GGAAACACAACTATGTGTCATGCTTTTATTTTCACATTATACTGAGGGGATATGACATTATAGAAACACA GTTTGTTCTTTGCATATGCTGAGAGAGGAACTAGATGAAGTGTGCTAATTCTTAGCAATAAAAAGATATA CAAAGTGGTACTTTACTGTTTCAATTTTTGTAACTGGCATCATTGTCTTTGATATTTTATATCTTCCTTG AGCACTGCCTTCTCTCAAGTGTCCAACTTCAGAGTATGCTATAGCAGGAAGACTACCAAATAAGATTAAT TTTTTTGTACCCATGAAAAAATTATGTGCCCTGACCCCTGTTCTCTGAAAGAGGAGCCAAGTTCTGGATT CCCAGATCCTCATATTCATTGATCAGCAGTGAACACAGATCATTCACCATGGACATGGGGCTCATCTGGA TTCTCCTTATTGTTTTTAAAAAAGGATTTCATTGGGAAAAGCTGCCTCATATTTCTATGACCAGGAGAGG AAGATACAGCTAGAGACACAAGCCCCACCATGTAAAATCTGTATGGTACTCTCGTTTTCATTTTACAACA TTTTGCTTTTGCATTGCAAAGGAGCAATAAGGGTTCAGCAATCAGCACTGTAACTGTACTTTTAAAATTT CCACCTCTACCCTCTGTGTCCTCTATCTAGTGATAGAAAGTGAAATAAGCACATAAAGCATGGGACAAGA AGAACACACAGAGGAGCAGAGACTGGCTACAAGTGGCAGCCAGCATGGAGCTGGACAGAATTTAAAAAGA TAAAGAGAAATGTCATGGCATGAAGCAGTGACTTTTTCTGTTCACAATGCCTGCAAAAACTTTATGGAGC CTACTACTGCTGAGATATGCAGGTTTGGTTCCAGAGAGGATTTTCTGTTTTATTTAATTTGCTTTTAAAT TTTTCTTCTTTGTATAGTCTGTATTTTTAAAAAGGGGTTGAATGAATACCTAAGCAGTTGGAAAATTTGT GAGTAGAAACCGAGGGCCTGAGAAACAAATAAATCAAAATTTTGAAATGGCAAAAGAAAGGGTTCATTCT ATTTTCTCTTTTCAGAAAAGGTTGCAAAGTTGGATGTGCAAATGGAGATGTTATGGGTGGACTTGGAACA TCTTGGGAAGGAAGGAACCCAGGAAAAGAAAGAATGAAATGGCTCAGCCTCAATGACTGAGCAAGAGAGT TAGAGTCACCCACAGGAGAAAAGAAGAAAATAAACAGCACTGGGGTGAATTTGGGTCAGAGAAAACCTTA AAATGCCAGAGGACAATGTGATGAAAGAGACCATTTGAAAGAAAGGGTTAACCTCATTCCATCAGTCATG CCAGAGTTAGAGAATGGGCAGTCTGGAGTTACAAGATCACGATTAGCCTTCCCAGTATGTATACAGCATA TTCCTGATAATGAGATGAAGCAAAGTTTGACAAGGTAAGATTGTATCCTATAGTAATATATAGATCAAAG GCATGTTGCAGTAAATCTCCAACAGAAATAAGCCCGGGCAATGAAAACACAACTCAATTAATATGAATAC GTGCTGTGCACCTAGACTGGGCAGATCTACCACTCCACTACCATATGAGAGATCCCTTATAACTTGTGGT TTCTCCAGGCCAGCTGCTTCTGCTCTACTTTCCTTCCTCCTCCTCCTATGTCATCCTCTCCCTCACTCTT TCTCTCCCAAAACTTTCAGCTGCACCTTCCCCTCTTCATCCCCCAATCAGTGGCTCTAGCCTTTATTTAT AAATTAAGGTAGGAAGAAGGTTTATAGGAAATTACCTGAGTGTTGACGTGTTGATAACCCCACACAAGAG AACAAAATTAATATCAAATATGATTAGCTCCAGGGTTATATGCAACAAAGGCATGATAAAGTGGTCATGA TTTCATATGAGATGTACTGGACTCATGTGAAAAAACGTTTAAATACATGGGCTTACTCAAAATATAGACT CATACCCCCAAGATGGGAAGAGACTGGTAACATTTGTACTGGAGGCTGGTCTGCTGTGGCAGCCATTAAC ACAGTGGAGGGAAGAGCCTCAAAGAGTGAAATAGAGGAAGGGGAACAAATACAGTAAACCACCAGTTACT ACTTAAAGGGCAGTGTTCTGATGTCCTAGGGAGGGCACTCCAAAATACCAATGGCCTTATCCTTAAATTT ATTGTTTAATGAGCCTACACTGATCTCAGTGGCCCACTACTAAGGAGAAATGACAGGCACTTGAACAGCT GATATGAGAACAGCTGGAGGCACAGTATACAGAAGAGTTTACAAGCCTATGGAACTCCCCTGTATTTTTT TATGATGAGGAAATCTGAAAAATGTAAAATGTTGAAAGATTTAAGAGCAGTTATTAGAGTAGATCAACCA ATGAGTCTCTTGCAGCCTGGAATTCTTTTATCTTGTTTGTAACAACAATCAGGCTCCATAAATTATAAAC TATAAAAATTTACTTTATAAATTATAAATATATATATATGTGTGTCTGTAGATAGATAGATAGATAAATA GATAGATAGATAGATAGATAGATAGATAGATATATGGATTTGATGGTTGCAGCAAATTCTAATTGGTTCC AACAACCCTACTCACATAATACATTCATACAGGTTTGATAGATGGAGCTAAGTTTTAAATAAATTATTTT TCTCCCATGGCTTATATATACACCACCAAAATTCTCAAAAATTAAAATGTGATTGTGTTGTATTTTTCTT TTACTGAATGACTATAAAAAGTTACAACATTCTCCATAAATTTACATGAAAAAATATTATGTAGTGCAGG TAAAGAAAACAAATTGACCCAAGAATGGTGTATATTCATTACTAAGCAACTTTTTAGATTCACAAAGTGT GGGTAAACAAGGTAATTTTTTCAATCAGTTTTTTTTAACTGGCAGGCAGCAATTCAGAGTTACAATGAGA AGATTAATAATTTTATTGTGTATTTTAAAATAAATCTTACAAAAATATTAATAGAATCACAAATTTATAC CTTTGTATAAAAACAATCAGTCATTTCTACTTTAAGAAACAGAACTCACATCTACTCATCAATCATTTTA TTAAGTCATATTACAAAGCTGAGTGCTAACATGGGTATAAGAAAACCATAACCTTATTCACCAGCCCAGC GTCAAAAAGAAAAAAACCAGTCATATCAGCTGCTGCTTCAAGAGTTCTTGTTCCTTGACATTAACAAAAT CCCTAGCTTAACTATTAAATTTTTTTTCAAAACTTCTAATTGATCCCTTAGATAAATGTTTGTGCTAACC ATCGGGACACATCCCATGAGTTCTGAAGCAGTGTGTTGTTCTTCATGCATGGCCCTTTTGTAGAGCTGTG AGTGTAGGGGAAGAGGGGGGAGAGAGAGCCCGTGTCCAGCCAGAGATCCTGTGCTCTGGGCAGGCAGACA CGGGAGGACAACGGAACACTTTTCACTCGGCCTTTGGTGGGCATCTGGCTGTGTGAAGTTACTGACCCCA CATGGTGGGGGATGGACAAGGGGCAGCCCCTGGTACCAGGAGCCCCAGGGCTACACTCTCGGCCCCAGAT ATACAAGAAGAGGGCAGAGGGAGAGAGGCTCCCACACAGGCGAGAGTCCTTAGTCTGGTCTGTGGCTGGA GCAGGGGAATTCCTTCTGATTGGAGATTAGGCACAGCTGATTAGGGGAAAGCCTACCCCATCATCCAAGC ACAATGGACTTTGAGGAACAGAGCCAGTCTAAGCTTTTATAGCTTTATGGTAGAAAGGCAGGGAGAAAGG AGAGAATGTGGAGAGAGACAGAGAGAGACTGGCCATGGCCAAGAGGAGGGAAGGGGGAAGAGAGAGAAAC AGGAAAAGCTAGAAAGTAAGATAAGAGAAAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGCAAAGTG GGGCCAAGCAGCCCCTTTTCTAGTGAGCTTGTCATCTCACAGTTGCTAGGTAACTGGGGAGGAGTTTAGT CTGAAGGTCAGAAGCTTGGGACCTTGTGTATGTGACTACTAACCACAGCTTCTCCTGTCGGGACTGTGGG AGCAGTAACTTTGACAGGAGACAGGGATCCAGGAGACATGAGGGAACACCTTCTGTCCCACATAGGTGGA ATCGGTTGTACCAGGGTTCAGAACTCAACTCCACTGGAGACCAGCCTATGTGTGCATAGCCCATTGCCCT ACAGCCTTTGACATTCTACAGAGTTCTGAGACTGGTAGAGATACAAAATAGCTAGGATTACACAGAGAAA CACTGGCTTGACAATAAAACTTCCAAAACAAATATAAATGAATAAATACACAAATTGGAGCAAGTGAACT TGCACTAAATCCATCAAAACTTGCACAGGATGGCTGTCTCCATAATGTTCAGATCTACTTCTATTAATGT CATTAAGAAGACAAAGATTATGCACAAAAAGAAACAAAACAAGAAACCCAAAAGGTAAAGGCTCCAATTG TAAGTAATAGACCCACAGTCTCTGAGGCCTGACTGTGCAGGTCCTCACCTTTGGTAATCAGCACTGAATG CAGACCACTCCTCATGGACTTTGGGCTCAGGTTTGTTTTCCTTGTCCTTATTTTAAAAGGTAATTCATAG AAATGAGATCCTGCCAGTATTGTGTACATGAGAAATAGAAAAATTGGTTTTCTTTGCTCTATTTTGTTTT GTTTGGTTAATGACAGTTTCCAAATCAGCATTCTTTGCTTTGAGGTGCCCAGTGTGAGGTGAAGCTGGTA GGGTCAGGGCAGCCTGGAGGGTCCCTGAAACACTCCTGTGCAGCCTCTGTAGTCACTGTGAGTGACTACT GAATGACCTGGGTCCTTCAGGCTCTAAAGAAGGGGCTGGAGAGGGTGGAAATAATTTTTAATGGTGGAGG TAGCACCTATTATCCAGACACCATGAAGGGCTGATTCACCATCTACAGAGATGATGCCAGAAACACACTT TACCTGAAAATAAACAGTCTGAGGTCTGAGTACACAGCCATGTGTGTGTGTGTGTGTGTGTGTGTGTGTG TGTGTGTGTGTGTGTGTGTGTGTGAGTGTGTATTCATATATATATATATAGTGTGTATGTATATTCATAT ATATATGTATATTCATAAGGTTGAGTAAATGGACTTAAACTGATTCCATCACAACTTCCATGGGATGGAT ATTTCCCAGTGTTAAGACCTGTCAACATCACTGTCATTCAGGAGACAATGATTATGCACAACAAAACAAG AAACCCAAAAGCAGAGGACTCCAATTACAATAGACCCAGACCCACAGTCTCTGAAGATTGACTGTACAGT TCAACCCAGCCCTGTACTTCTCTTCCCTAGAATTTACATTACTGAGTAACTGAGGAAAGCTCTACAATAT CTGTTCTCTATAGTGGTCAACACCTCCAAACACAGGTTACCCATATTCATGCCTGCCTTCTGCTACACTT CTTGCCATAATGTAGACTACTTCAGCCTATTTTGTACTCCAGTTAACGAAACTCAAGACTAGCTGCATGT TAGTCCTTATTCTGAAATATTATGAACAGGTGACCTCCCATCATTCACCAATGCAATAATCATATTTAGG AATATGAGGTTTTATGAGATATAAGCACAAGGGAGAGAAAGTAAGAAAACTACATAGATATATAGACTGA CATAAATCAAGACTTGCATGAGCTAGTGCCCAAGTACCATGTCCCTAAGTGGCAAGGAGTATCTTTTGAG CCTAGTGAGATGAGGTACAAATCGGACTCTTACATCTTTTTAGATAAACATGTGAGATCAATGGACTAAA GGCGTGAGCTGGGCTTCCTTGCAATCCATTTTCCATACAAGATAACAATAGATCTGGCTCCACAGACACG ATGAGAATAGTCTTAATTAGTTCTTTAAGTAGAATGACTGATCACTAAGAGCCCAATTCCATACTAAATA CTCTTCTGGATTATGCACAGATAAAAATTGCACATAGGGCATGGGGCACTGATCTCCCTGCACTACATGA ATGGGGGCTCATTTACTAAATGTTCCCATGTTTCTTCCTAGTGCTGCACAGAGCAAATCCTACAACTTCC TGCTTGTCTACAATGTAAACTCCAGACAGTACCAGAAAATCATTCCTTATGTTCCTCTCCAGGTGCTTCA ACAAGCACAGTGCAAATTTCTGTCACCCTG Vaximmutor Vaximmutor SfbI Streptococcus pyogenes DSM 2071 VO_0012394 511149 WP_014407228 CAA48133.1 CDD:311998 CDD:331285 CDD:308566 1314 ? fibronectin-binding protein SfbI 4.15 64222.46 694 Thioester domain; pfam08341 >gi|511149|emb|X67947.1| S.pyogenes Sfb gene for fibronectin-binding protein (partial) TAAAGCAATATTTTCTCAAAAAATCATTTTCAAAAACATTAATTTGGTGAAAAATATAATCAAAAAATTG TCTTTCTTGACAATAACGTGGTAAGCTCATATATGTTTGTGAGAGGAGAGAAAATGAATAACAAAATGTT TTTGAACAAAGAAGCCGGTTTTTTGGCACACACAAAAAGAAAAAGGCGATTTGCTGTCACTTTAGTGGGA GTCTTTTTTATGCTTTTGGCATCCGCGGGTGCTATCGGTTTTGGTCAAGTAGCCTATGCTGCCGATGAGA AGACTGTGCCTCATAGAGTTAGTCAAAATCCTGAGTTTCCCTGGTATGGTTATGATTTCTACAAAGGACC TTACACAAGATATCATAATTTACAGCTAAATCTCAACGGAAGTAAAACATATCAGGCTTATTGTTTTAAT TTAAAGAGATTTGAACCTAAGAAAGAAGGTAGTTATTTTCCGAATTGGTATAAGAGGTGGGATGGTAGTG AAGAGACATTTGTAAAATATGCTGATAACCCCAGAAAAGATAATGAAAGTTCCAGAGTTATAGATGTAGA ATTAGAAAAAAATATATTAAGAGTGCTATATAATGGATATCCGAATAACGGTAATGGAATCATGGAGGGT TTAGAACCATTAAATGCTATCTTAGTAACTCAAAATGCTGTTTGGTACTATTCTGATAATTCATCTATTT TTAATACTGATAACTTCTTTACGACTGAAGCTAAAGATCTTAATATAAAACCTGAGCAATTATCATTAAT GCGTGTTGCATTAAAGAAATTGATAGATCCTAAGTTATCTGAAGAATCATTGAAACCTGTGCCATCTACT TTTAGACTGAATATTTTCGAATCTCAGGATAAGCTATATCAAAATCTTCTAAGTGCTGAGTTTGTACCAG AAAATCCCCCTAAACCTGGTGAAACCCCTGAACATGGACCCAAAACTCCCGAGTTGGATGGCACTCCAAT TCCCGAAGGCCCACAACGTCCAAATGAGAGTTTAGAACCTACGCTTCCACCAGTGATGCTAGACGGACAA GAAGTCCCCGAAGTTCCAAGTGAGAGCTTAGAACCTGCGCTTCCCCCATTGATGCCAGAGCTAGATGGCC AAGAAGTCCCAGAAGTTCCAAGCGAGAGCTTAGAACCTGCGCTTCCCCCATTGATGCCAGAGTTAGATGG TCAAGAAGTCCCTGAAAAACCTAGTGTTGACTTACCTATTGAAGATCCTCGTTATGAGTTTAACAATAAA GACCAATCACCTCTAGCGGGTGAGTCTGGTGAGACGGAGTATATTACCGAAGTTTATGGAAATCAACAGA ACCCTGTTGATATTGATAAAAAACTTCCGAATGAAACAGGTTTTTCAGGAAATATGGTTGAGACAGAAGA TACGAAAGAGCCAGGAGTGTTGATGGGAGGTCAAAGTGAGTCTGTTGAATTTACTAAAGACACTCAAACA GGCATGAGTGGTCAAACAACTCCTCAGGTTGAGACAGAAGACACGAAAGAGCCAGGAGTGCTGATGGGAG GTCAAAGTGAGTCTGTTGAATTTACCAAAGATACTCAAACAGGCATGAGTGGTCAAACAGCTTCTCAGGT TGAGACAGAAGATACGAAAGAGCCAGGAGTGCTGATGGGAGGCCAAAGTGAGTCTGTTGAATTTACTAAA GACACTCAAACAGGCATGAGTGGTCAAACAACTCCTCAGGTTGAGACAGAAGACACGAAAGAGCCAGGAG TATTGATGGGAGGTCAAAGTGAATCTGTTGAATTTACTAAAGACACTCAAACAGGCATGAGCGGTTTCAG TGAAACAGTGACCATTGTTGAAGATACCCGTCCGAAGTTAGTGTTCCATTTTGACAATAATGAGCCCAAA GTGGAAGAGAATCGGGAAAAGCCTACAAAAAATATAACACCTATCCTTCCTGCAACAGGAGATATTGAGA ATGTTTTGGCCTTTCTTGGAATCCTTATTTTGTCAGTACTTCCTATTTTTAGTCTTTTAAAAAAACAAAC AAAACAATAAAGTCTGATCGTAAAAGTGTTCCATAAGAAATAATGCGCAAATATGCTGAATAGTGGATAA CTGCTACAGTCAAGACAAGTGTTAATTCAAAAGGTACTACTTATACATCTGATAATAATAAGGTGACAGA TAATTCAGAGCAAGTAGGATGGCTAAAAAATGGTGTATTCTATGTATAATAGACTACATAGAAATCAAGT TATTGTTAAACGTCGTAAAGCTT >WP_014407228.1 fibronectin-binding protein SfbI [Streptococcus pyogenes] MNNKIFLNKEAGFLAHTKRKRRFAVTLVGVFFMLLACAGAIGFGQVAYAADERTVPNHSSTNPEFPWYGY DSYRGIFARYHNLKVNLKGSKEYQAYCFNLTKYFPRPTYSTTNNFYKKIDGSGSAFKSYAANPRVLDENL DKLEKNILNVIYNGYKSNANGFMNGIEDLNAILVTQNAIWYYSDSAPLNDVNKMWEREVRNGEISESQVT LMREALKKLIDPNLEATAVNKIPSGYRLNIFKSENEDYQNLLSAEYVPDDPPKPGDTSEHNPKTPELDGS PIPEDPKHPDDNLEPTLPPVMLDGEEVPEVPSESLEPALPPLMPELDGEEVPEVPSESLEPALPPLMPEL DGEEVPEVPSESLEPALPSLMPELDGEEVPEVPSESLEPAFPPLMPELDGQEVPEKPSVDLPIEVPRYEF NNKDQSPLAGESGETEYITEVYGNQQNPVDIDKKLPNETGFSGNMVETEDTKEPEVLMGGQSESVEFTKD TQTGMSGQTTPQVETEDTKEPGVLMGGQSESVEFTKDTQTGMSGFSETVTIVEDTRPKLVFHFDNNEPKV EENREKPTKNIAPILPATGDIGNVLAFLGILILSVLSIFSLLKNKQNNKV Protective antigen Intranasal immunization of mice with either SfbI alone or coupled to cholera toxin B subunit (CTB) triggered efficient SfbI-specific humoral (mainly IgG) and lung mucosal (14% of total IgA) responses. SfbI-vaccinated animals showed 80% and 90% protection against homologous and heterologous challenge, respectively [Ref1507:Guzmán et al., 1999]. Peptides incorporated in the Lipid-Core Peptide (LCP) vaccine delivery system derived from the important streptococcal virulence factors M protein and the fibronectin-binding protein SfbI. The present work clearly demonstrates the potential of these synthetic dual antigen multi-epitope mucosal GAS prophylactic vaccines as an approach to deliver vaccine antigens and adjuvants across mucosal membranes resulting in the stimulation of protective immune responses.[Ref4816:Schulze et al., 2017] sib35 Streptococcus pyogenes serotype M12 VO_0012398 90567992 CDD:286161 342023 ? immunoglobulin-binding protein 35 7.68 36275.97 431 Mac 1; pfam09028 >BAE92207.1 immunoglobulin-binding protein 35 [Streptococcus pyogenes serotype M12] MRKRCYSTSAAVLAAVTLFVLSVDRGVIADSFSANQEIRYSEVTPYHVTSVWTKGVTPPAKFTQGEDVFH APYVAKQGWYDITKTFNGKDDLLCGAATAGNMLHWWFDQNNEKIEAYLKKHPDKQKIMFGDQELLDVRKV INTKGDQTNSELFNYFRDKAFPGLSARRIGVMPDLVLDMFINGYYLNVYKTQTTDVNRTYQEKDRRGGIF DAVFTRGDQSKLLTSRHDFKEKTLKEISDLIKKELTEGKALGLSHTYANVRINHVINLWGADFDSNGNLE AIYVTDSDSNASIGMKKYFVGVNSAGKVAISAKEIKEDNIGAQVLGLFTLSTGQDSWNQTN Protective antigen Immunization with Sib 35 enhanced survival rates in mice challenged with a GAS strain, while exhibiting no toxicity in hosts [Ref1511:Okamoto et al., 2005]. Bensi et al., 2012 journal Bensi G, Mora M, Tuscano G, Biagini M, Chiarot E, Bombaci M, Capo S, Falugi F, Manetti AG, Donato P, Swennen E, Gallotta M, Garibaldi M, Pinto V, Chiappini N, Musser JM, Janulczyk R, Mariani M, Scarselli M, Telford JL, Grifantini R, Norais N, Margarit I, Grandi G 2012 11 6 M111.015693 Molecular & cellular proteomics : MCP Chen et al., 2016 journal Chen X, Li N, Bi S, Wang X, Wang B 2016 11 12 e0168861 PloS one Courtney et al., 2017 journal Courtney HS, Niedermeyer SE, Penfound TA, Hohn CM, Greeley A, Dale JB 2017 6 1 45-49 Clinical and experimental vaccine research Dale et al., 2015 journal Dale JB, Niedermeyer SE, Agbaosi T, Hysmith ND, Penfound TA, Hohn CM, Pullen M, Bright MI, Murrell DS, Shenep LE, Courtney HS 2015 22 3 344-350 Clinical and vaccine immunology : CVI Guerino et al., 2011 journal Guerino MT, Postol E, Demarchi LM, Martins CO, Mundel LR, Kalil J, Guilherme L 2011 29 46 8250-8256 Vaccine Guzmán et al., 1999 journal Guzmán CA, Talay SR, Molinari G, Medina E, Chhatwal GS 1999 179 4 901-906 The Journal of infectious diseases Kagawa et al., 2009 journal Kagawa TF, O'Connell MR, Mouat P, Paoli M, O'Toole PW, Cooney JC 2009 386 3 754-772 Journal of molecular biology Kawabata et al., 2001 journal Kawabata S, Kunitomo E, Terao Y, Nakagawa I, Kikuchi K, Totsuka K, Hamada S 2001 69 2 924-930 Infection and immunity Kawabata et al., 2001 journal Kawabata S, Kunitomo E, Terao Y, Nakagawa I, Kikuchi K, Totsuka K, Hamada S 2001 69 2 924-930 Infection and immunity Kotloff et al., 2004 journal Kotloff KL, Corretti M, Palmer K, Campbell JD, Reddish MA, Hu MC, Wasserman SS, Dale JB 2004 292 6 709-715 JAMA : the journal of the American Medical Association Lei et al., 2004 journal Lei B, Liu M, Chesney GL, Musser JM 2004 189 1 79-89 The Journal of infectious diseases Ma et al., 2009 journal Ma CQ, Li CH, Wang XR, Zeng RH, Yin XL, Feng HD, Wei L 2009 6 1 73-77 Cellular & molecular immunology Ma et al., 2014 journal Ma C, Liu Z, Li W, Qian X, Zhang S, Gao X, Jiang S, Wei L 2014 16 5 409-418 Microbes and infection Mansour and Abdelaziz, 2016 journal Mansour NM, Abdelaziz SA 2016 60 8 527-532 Microbiology and immunology McNeil et al., 2005 journal McNeil SA, Halperin SA, Langley JM, Smith B, Warren A, Sharratt GP, Baxendale DM, Reddish MA, Hu MC, Stroop SD, Linden J, Fries LF, Vink PE, Dale JB 2005 41 8 1114-1122 Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Morefield et al., 2014 journal Morefield G, Touhey G, Lu F, Dunham A, HogenEsch H 2014 32 30 3810-3815 Vaccine Mortensen et al., 2016 journal Mortensen R, Nissen TN, Fredslund S, Rosenkrands I, Christensen JP, Andersen P, Dietrich J 2016 6 22030 Scientific reports Niedermeyer et al., 2014 journal Niedermeyer SE, Penfound TA, Hohn C, Li Y, Homayouni R, Zhao J, Dale JB 2014 21 10 1421-1425 Clinical and vaccine immunology : CVI Okamoto et al., 2005 journal Okamoto S, Tamura Y, Terao Y, Hamada S, Kawabata S 2005 23 40 4852-4859 Vaccine Okamoto et al., 2005 journal Okamoto S, Tamura Y, Terao Y, Hamada S, Kawabata S 2005 23 40 4852-4859 Vaccine Pandey et al., 2015 journal Pandey M, Langshaw E, Hartas J, Lam A, Batzloff MR, Good MF 2015 194 12 5915-5925 Journal of immunology (Baltimore, Md. : 1950) Poirier et al., 1988 journal Poirier TP, Kehoe MA, Beachey EH 1988 168 1 25-32 The Journal of experimental medicine Radcliff et al., 2015 journal Radcliff FJ, Fraser JD, Proft T 2015 204 2 185-191 Medical microbiology and immunology Reglinski et al., 2016 journal Reglinski M, Lynskey NN, Choi YJ, Edwards RJ, Sriskandan S 2016 72 4 450-459 The Journal of infection Rivera-Hernandez et al., 2016 journal Rivera-Hernandez T, Pandey M, Henningham A, Cole J, Choudhury B, Cork AJ, Gillen CM, Ghaffar KA, West NP, Silvestri G, Good MF, Moyle PM, Toth I, Nizet V, Batzloff MR, Walker MJ 2016 7 3 mBio Rodríguez-Ortega et al., 2006 journal Rodríguez-Ortega MJ, Norais N, Bensi G, Liberatori S, Capo S, Mora M, Scarselli M, Doro F, Ferrari G, Garaguso I, Maggi T, Neumann A, Covre A, Telford JL, Grandi G 2006 24 2 191-197 Nature biotechnology Sagar et al., 2012 journal Sagar V, Bergmann R, Nerlich A, McMillan DJ, Nitsche Schmitz DP, Chhatwal GS 2012 19 11 1818-1825 Clinical and vaccine immunology : CVI Schulze et al., 2006 journal Schulze K, Olive C, Ebensen T, Guzmán CA 2006 24 35-36 6088-6095 Vaccine Schulze et al., 2017 journal Schulze K, Ebensen T, Chandrudu S, Skwarczynski M, Toth I, Olive C, Guzman CA 2017 13 8 2463-2474 Nanomedicine : nanotechnology, biology, and medicine Severin et al., 2007 journal Severin A, Nickbarg E, Wooters J, Quazi SA, Matsuka YV, Murphy E, Moutsatsos IK, Zagursky RJ, Olmsted SB 2007 189 5 1514-1522 Journal of bacteriology Textbook of Bacteriology website http://textbookofbacteriology.net/streptococcus Tsao et al., 2013 journal Tsao N, Cheng MH, Yang HC, Wang YC, Liu YL, Kuo CF 2013 8 1 e55028 PloS one Wiki: S. pyogenes website http://en.wikipedia.org/wiki/Streptococcus_pyogenes Zhang et al., 2006 journal Zhang S, Green NM, Sitkiewicz I, Lefebvre RB, Musser JM 2006 74 7 4200-4213 Infection and immunity Zhang et al., 2017 journal Zhang X, Song Y, Li Y, Cai M, Meng Y, Zhu H 2017 973 115-124 Advances in experimental medicine and biology