Ltr retrotransposon compositions and methods

Abstract

Methods and compositions for altering a genome at one or more locations in a host cell, tissue, or subject are disclosed.

Description

Attorney Docket No.: 2017469-0045 LTR RETROTRANSPOSON COMPOSITIONS AND METHODS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to United States Provisional Application No. 63 / 656,997, filed June 6, 2024, the entirety of which is incorporated herein by reference. BACKGROUND

[0002] Integration of a nucleic acid of interest into a genome occurs at low frequency and with little site specificity, in the absence of a specialized protein to promote the insertion event. Some existing approaches, like CRISPR / Cas9, are more suited for small edits and are less effective at integrating longer sequences. Other existing approaches, like Cre / loxP, require a first step of inserting a loxP site into the genome and then a second step of inserting a sequence of interest into the loxP site. There is a need in the art for improved proteins for inserting sequences of interest into a genome. SUMMARY OF THE INVENTION

[0003] This disclosure relates to novel compositions, systems, and methods for altering a genome at one or more locations in a host cell, tissue, or subject, in vivo or in vitro. In particular, the invention features compositions, systems, and methods for the introduction of exogenous genetic elements into a host genome. The systems described herein typically include a template RNA comprising a pair of long terminal repeats (LTRs) flanking a heterologous object sequence (e.g., encoding a therapeutic effector), which can be introduced into a target cell with a structural polypeptide domain and a reverse transcriptase polypeptide domain, or nucleic acid molecules encoding same. Inside the cell, the template RNA and reverse transcriptase polypeptide domain can be enclosed within a proteinaceous exterior (e.g., a capsid), e.g., to form a virus-like particle (VLP). The reverse transcriptase polypeptide domain can then generate a template DNA from the template RNA. The resultant template DNA can then be integrated into the genome of the cell, e.g., by an integrase from a retrovirus or a retrotransposon, e.g., an LTR retrotransposon. Additionally described here are integration-deficient systems for providing an extrachromosomal DNA molecule to a host cell that does not undergo genomic integration. Thus, this disclosure provides systems capable of producing therapeutic DNA in a host cell, e.g., DNA encoding a Page 1 of 356 12806819v1Attorney Docket No.: 2017469-0045 therapeutic protein, by reverse transcription of an RNA template comprising LTRs, wherein the therapeutic DNA is optionally integrated into the host genome.

[0004] Features of the compositions or methods can include one or more of the following enumerated embodiments. 1. A template RNA comprising: a 5’ long terminal repeat (5’ LTR) having a sequence according to column 3 of Table G, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; a 3’ long terminal repeat (3’ LTR) having a sequence according to column 5 of the same row of Table G as the 5’ LTR, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; a heterologous object sequence encoding a therapeutic effector, positioned between the 5’ LTR and the 3’ LTR; and a primer binding site (PBS). 2. A system for modifying DNA comprising: a) a template RNA of embodiment 1, or a DNA molecule encoding the template RNA; and b) a polypeptide driver having an amino acid sequence according to Table B that corresponds to the 5’ LTR and 3’ LTR, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; or a nucleic acid molecule or a plurality of nucleic acid molecules encoding the polypeptide driver. 3. The system of embodiment 2, wherein the polypeptide driver further comprises an amino acid sequence according to Table C that corresponds to the 5’ LTR and 3’ LTR, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 4. The system of embodiment 3, wherein the polypeptide driver further comprises an amino acid sequence according to Table D that corresponds to the 5’ LTR and 3’ LTR, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. Page 2 of 356 12806819v1Attorney Docket No.: 2017469-0045 5. The system of embodiment 4, wherein the polypeptide driver further comprises an amino acid sequence according to Table E that corresponds to the 5’ LTR and 3’ LTR, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 6. The system of embodiment 5, wherein the polypeptide driver further comprises an amino acid sequence according to Table F that corresponds to the 5’ LTR and 3’ LTR, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 7. The system of any one of embodiments 2-6, wherein the template RNA and the nucleic acid encoding the polypeptide driver are separate nucleic acids. 8. The system of any one of embodiments 2-7, wherein the template RNA and the nucleic acid encoding the polypeptide driver are present in the same nucleic acid. 9. A polypeptide driver having an amino acid sequence according to Table B, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 10. The polypeptide driver of embodiment 9, which further comprises an amino acid sequence according to Table C that corresponds to the sequence of Table B, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 11. The polypeptide driver of embodiment 9 or 10, which further comprises an amino acid sequence according to Table D that corresponds to the sequence of Table B, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 12. The polypeptide driver of any one of embodiments 9-11, which further comprises an amino acid sequence according to Table E that corresponds to the sequence of Table B, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. Page 3 of 356 12806819v1Attorney Docket No.: 2017469-0045 13. The polypeptide driver of any one of embodiments 9-12, which further comprises an amino acid sequence according to Table F that corresponds to the sequence of Table B, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 14. A polypeptide driver having an amino acid sequence according to Table C, D, E, or F, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 15. The system or polypeptide driver of any one of embodiments 3-14, wherein the sequence of Table B and the sequence of Table C are in separate polypeptide chains. 16. The system or polypeptide driver of any one of embodiments 2-15, wherein the sequence of Table B and the sequence of Table C are fused in a single polypeptide chain. 17. The system or polypeptide driver of any one of embodiments 3-14, wherein the sequence of Table B, the sequence of Table C, and the sequence of Table D are in separate polypeptide chains. 18. The system or polypeptide driver of any one of embodiments 4-14, wherein the sequence of Table B, the sequence of Table C, and the sequence of Table D are fused in a single polypeptide chain. 19. The system or polypeptide driver of any one of embodiments 5-14, wherein the sequence of Table B, the sequence of Table C, the sequence of Table D, and the sequence of Table E are in separate polypeptide chains. 20. The system or polypeptide driver of any one of embodiments 5-14, wherein the sequence of Table B, the sequence of Table C, the sequence of Table D, and the sequence of Table E are fused in a single polypeptide chain. Page 4 of 356 12806819v1Attorney Docket No.: 2017469-0045 21. The system or polypeptide driver of any one of embodiments 6-14, wherein the sequence of Table B, the sequence of Table C, the sequence of Table D, the sequence of Table E, and the sequence of Table F are in separate polypeptide chains. 22. The system or polypeptide driver of any one of embodiments 5-14, wherein the sequence of Table B, the sequence of Table C, the sequence of Table D, the sequence of Table E, and the sequence of Table F are fused in a single polypeptide chain. 23. The template RNA or system of any one of the preceding embodiments, wherein the PBS is situated between the 5’ LTR and the heterologous object sequence. 24. The template RNA or system of any one of the preceding embodiments, wherein the PBS has a sequence according to Table H, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 25. The template RNA or system of any one of the preceding embodiments, wherein the PBS has a sequence according to Table Z, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 26. A nucleic acid molecule or a plurality of nucleic acid molecules (e.g., mRNA) encoding the polypeptide driver of any one of embodiments 9-22. 27. The template RNA or system of any one of embodiments 1-25, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 229, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 267, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 28. The system of embodiment 27, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 39, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. Page 5 of 356 12806819v1Attorney Docket No.: 2017469-0045 29. The template RNA or system of embodiment 27 or 28, wherein the PBS has a nucleotide sequence of SEQ ID NO: 305 or SEQ ID NO: 343, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 30. The template RNA or system of any one of embodiments 1-25, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 230, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 268, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 31. The system of embodiment 30, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 40, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 32. The system of embodiment 30, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 40, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto, and an amino acid sequence of SEQ ID NO: 78, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 33. The template RNA or system of embodiment 30 or the system of 31 or 32, wherein the PBS has a nucleotide sequence of SEQ ID NO: 306 or SEQ ID NO: 344, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 34. The template RNA or system of any one of embodiments 1-25, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 231, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 269, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. Page 6 of 356 12806819v1Attorney Docket No.: 2017469-0045 35. The system of embodiment 34, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 41, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 36. The system of embodiment 34, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 41, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto, an amino acid sequence of SEQ ID NO: 79, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; an amino acid sequence of SEQ ID NO: 117, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; an amino acid sequence of SEQ ID NO: 155, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 193, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 37. The template RNA or system of embodiment 34 or the system of 35 or 36, wherein the PBS has a nucleotide sequence of SEQ ID NO: 307 or SEQ ID NO: 345, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 38. The template RNA or system of and one of embodiments 1-25, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 232, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 270, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 39. The system of embodiment 38, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 42, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. Page 7 of 356 12806819v1Attorney Docket No.: 2017469-0045 40. The system of embodiment 38, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 42, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto, and / or an amino acid sequence of SEQ ID NO: 80, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 41. The template RNA or system of embodiment 38 or the system of 39 or 40, wherein the PBS has a nucleotide sequence of SEQ ID NO: 308 or SEQ ID NO: 346, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 42. The template RNA or system of any one of embodiments 1-25, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 233, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 271, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 43. The system of embodiment 42, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 43, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 44. The system of embodiment 42, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 43, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 81, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. Page 8 of 356 12806819v1Attorney Docket No.: 2017469-0045 45. The template RNA or system of embodiment 42 or the system of 43 or 44, wherein the PBS has a nucleotide sequence of SEQ ID NO: 309 or SEQ ID NO: 347, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 46. The template RNA or system of any one of embodiments 1-25, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 234, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 272, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 47. The system of embodiment 46, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 44, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 48. The template RNA or system of embodiment 46 or the system of 47, wherein the PBS has a nucleotide sequence of SEQ ID NO: 310 or SEQ ID NO: 348, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 49. The template RNA or system of any one of embodiments 1-25, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 235, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 273, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 50. The system of embodiment 49, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 45, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 51. The template RNA or system of embodiment 49 or the system of 50, wherein the PBS has a nucleotide sequence of SEQ ID NO: 311 or SEQ ID NO: 349, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. Page 9 of 356 12806819v1Attorney Docket No.: 2017469-0045 52. The template RNA or system of any one of embodiments 1-25, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 236, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 274, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 53. The system of embodiment 52, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 46, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 54. The template RNA or system of embodiment 52 or the system of 53, wherein the PBS has a nucleotide sequence of SEQ ID NO: 312 or SEQ ID NO: 350, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 55. The template RNA or system of any one of embodiments 1-25, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 237, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 275, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 56. The system of embodiment 55, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 47, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 57. The system of embodiment 55, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 47, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 85, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. Page 10 of 356 12806819v1Attorney Docket No.: 2017469-0045 58. The template RNA or system of embodiment 55 or the system of 56 or 57, wherein the PBS has a nucleotide sequence of SEQ ID NO: 313 or SEQ ID NO: 351, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 59. The template RNA or system of any one of embodiments 1-25, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 238, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 276, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 60. The system of embodiment 59, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 48, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 61. The system of embodiment 59, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 48, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; an amino acid sequence of SEQ ID NO: 86, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 124, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 62. The template RNA or system of embodiment 59 or the system of 60 or 61, wherein the PBS has a nucleotide sequence of SEQ ID NO: 314 or SEQ ID NO: 352, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 63. The template RNA or system of any one of embodiments 1-25, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 239, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and Page 11 of 356 12806819v1Attorney Docket No.: 2017469-0045 the 3’ LTR has a nucleotide sequence of SEQ ID NO: 277, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 64. The system of embodiment 63, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 49, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 65. The system of embodiment 63, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 49, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 87, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 66. The template RNA or system of embodiment 63 or the system of 64 or 65, wherein the PBS has a nucleotide sequence of SEQ ID NO: 315 or SEQ ID NO: 353, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 67. The template RNA or system of any one of embodiments 1-25, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 240, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 278, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 68. The system of embodiment 67, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 50, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 69. The system of embodiment 67, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): Page 12 of 356 12806819v1Attorney Docket No.: 2017469-0045 an amino acid sequence of SEQ ID NO: 50, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; an amino acid sequence of SEQ ID NO: 88, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 126, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 70. The template RNA or system of embodiment 67 or the system of 68 or 69, wherein the PBS has a nucleotide sequence of SEQ ID NO: 316 or SEQ ID NO: 354, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 71. The template RNA or system of any one of embodiments 1-25, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 241, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 279, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 72. The system of embodiment 71, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 51, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 73. The template RNA or system of embodiment 71 or the system of 72, wherein the PBS has a nucleotide sequence of SEQ ID NO: 317 or SEQ ID NO: 355, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 74. The template RNA or system of any one of embodiments 1-25, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 242, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 280, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. Page 13 of 356 12806819v1Attorney Docket No.: 2017469-0045 75. The system of embodiment 74, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 52, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 76. The system of embodiment 74, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 52, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; an amino acid sequence of SEQ ID NO: 90, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 128, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 77. The template RNA or system of embodiment 74 or the system of 75 or 76, wherein the PBS has a nucleotide sequence of SEQ ID NO: 318 or SEQ ID NO: 356, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 78. The template RNA or system of any one of embodiments 1-25, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 243, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 281, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 79. The system of embodiment 78, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 53, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 80. The system of embodiment 78, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 53, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or Page 14 of 356 12806819v1Attorney Docket No.: 2017469-0045 an amino acid sequence of SEQ ID NO: 91, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 81. The template RNA or system of embodiment 78 or the system of 79 or 80, wherein the PBS has a nucleotide sequence of SEQ ID NO: 319 or SEQ ID NO: 357, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 82. The template RNA or system of any one of embodiments 1-25, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 244, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 282, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 83. The system of embodiment 82, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 54, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 84. The system of embodiment 82, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 54, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; an amino acid sequence of SEQ ID NO: 92, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; an amino acid sequence of SEQ ID NO: 130, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; an amino acid sequence of SEQ ID NO: 168, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 206, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. Page 15 of 356 12806819v1Attorney Docket No.: 2017469-0045 85. The template RNA or system of embodiment 82 or the system of 83 or 84, wherein the PBS has a nucleotide sequence of SEQ ID NO: 320 or SEQ ID NO: 358, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 86. The template RNA or system of any one of embodiments 1-25, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 245, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 283, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 87. The system of embodiment 86, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 55, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 88. The template RNA or system of embodiment 86 or the system of 87, wherein the PBS has a nucleotide sequence of SEQ ID NO: 321 or SEQ ID NO: 359, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 89. The template RNA or system of any one of embodiments 1-25, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 246, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 284, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 90. The system of embodiment 89, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 56, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 91. The system of embodiment 89, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): Page 16 of 356 12806819v1Attorney Docket No.: 2017469-0045 an amino acid sequence of SEQ ID NO: 56, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; an amino acid sequence of SEQ ID NO: 94, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; an amino acid sequence of SEQ ID NO: 132, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 170, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 92. The template RNA or system of embodiment 89 or the system of 90 or 91, wherein the PBS has a nucleotide sequence of SEQ ID NO: 322 or SEQ ID NO: 360, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 93. The template RNA or system of any one of embodiments 1-25, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 247, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 285, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 94. The system of embodiment 93, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 57, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 95. The system of embodiment 93, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 57, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; an amino acid sequence of SEQ ID NO: 95, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 133, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. Page 17 of 356 12806819v1Attorney Docket No.: 2017469-0045 96. The template RNA or system of embodiment 93 or the system of 94 or 95, wherein the PBS has a nucleotide sequence of SEQ ID NO: 323 or SEQ ID NO: 361, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 97. The template RNA or system of any one of embodiments 1-25, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 248, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 286, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 98. The system of embodiment 97, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 58, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 99. The system of embodiment 97, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 58, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 96, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 100. The template RNA or system of embodiment 97 or the system of 98 or 99, wherein the PBS has a nucleotide sequence of SEQ ID NO: 324 or SEQ ID NO: 362, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 101. The template RNA or system of any one of embodiments 1-25, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 249, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 287, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. Page 18 of 356 12806819v1Attorney Docket No.: 2017469-0045 102. The system of embodiment 101, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 59, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 103. The system of embodiment 101, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 59, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; an amino acid sequence of SEQ ID NO: 97, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 135, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 104. The template RNA or system of embodiment 101 or the system of 102 or 103, wherein the PBS has a nucleotide sequence of SEQ ID NO: 325 or SEQ ID NO: 363, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 105. The template RNA or system of any one of embodiments 1-25, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 250, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 288, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 106. The system of embodiment 105, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 60, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 107. The system of embodiment 105, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): Page 19 of 356 12806819v1Attorney Docket No.: 2017469-0045 an amino acid sequence of SEQ ID NO: 60, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 98, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 108. The template RNA or system of embodiment 105 or the system of 106 or 107, wherein the PBS has a nucleotide sequence of SEQ ID NO: 326 or SEQ ID NO: 364, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 109. The template RNA or system of any one of embodiments 1-25, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 251, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 289, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 110. The system of embodiment 109, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 61, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 111. The system of embodiment 109, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 61, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 99, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 112. The template RNA or system of embodiment 109 or the system of 110 or 111, wherein the PBS has a nucleotide sequence of SEQ ID NO: 327 or SEQ ID NO: 365, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 113. The template RNA or system of any one of embodiments 1-25, wherein: Page 20 of 356 12806819v1Attorney Docket No.: 2017469-0045 the 5’ LTR has a nucleotide sequence of SEQ ID NO: 252, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 290, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 114. The system of embodiment 113, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 62, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 115. The system of embodiment 113, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 62, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 100, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 116. The template RNA or system of embodiment 113 or the system of 114 or 115, wherein the PBS has a nucleotide sequence of SEQ ID NO: 328 or SEQ ID NO: 366, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 117. The template RNA or system of any one of embodiments 1-25, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 253, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 291, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 118. The system of embodiment 117, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 63, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. Page 21 of 356 12806819v1Attorney Docket No.: 2017469-0045 119. The template RNA or system of embodiment 117 or the system of 118, wherein the PBS has a nucleotide sequence of SEQ ID NO: 329 or SEQ ID NO: 367, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 120. The template RNA or system of any one of embodiments 1-25, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 254, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 292, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 121. The system of embodiment 120, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 64, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 122. The system of embodiment 120, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 64, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; an amino acid sequence of SEQ ID NO: 102, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; an amino acid sequence of SEQ ID NO: 140, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 178, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 123. The template RNA or system of embodiment 120 or the system of 121 or 122, wherein the PBS has a nucleotide sequence of SEQ ID NO: 330 or SEQ ID NO: 368, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. Page 22 of 356 12806819v1Attorney Docket No.: 2017469-0045 124. The template RNA or system of any one of embodiments 1-25, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 255, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 293, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 125. The system of embodiment 124, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 65, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 126. The system of embodiment 124, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 65, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; an amino acid sequence of SEQ ID NO: 103, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 141, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 127. The template RNA or system of embodiment 124 or the system of 125 or 126, wherein the PBS has a nucleotide sequence of SEQ ID NO: 331 or SEQ ID NO: 369, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 128. The template RNA or system of any one of embodiments 1-25, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 256, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 294, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. Page 23 of 356 12806819v1Attorney Docket No.: 2017469-0045 129. The system of embodiment 128, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 66, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 130. The template RNA or system of embodiment 128 or the system of 129, wherein the PBS has a nucleotide sequence of SEQ ID NO: 332 or SEQ ID NO: 370, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 131. The template RNA or system of any one of embodiments 1-25, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 257, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 295, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 132. The system of embodiment 131, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 67, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 133. The system of embodiment 131, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 67, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 105, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 134. The template RNA or system of embodiment 131 or the system of 132 or 133, wherein the PBS has a nucleotide sequence of SEQ ID NO: 333 or SEQ ID NO: 371, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 135. The template RNA or system of any one of embodiments 1-25, wherein: Page 24 of 356 12806819v1Attorney Docket No.: 2017469-0045 the 5’ LTR has a nucleotide sequence of SEQ ID NO: 258, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 296, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 136. The system of embodiment 135, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 68, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 137. The system of embodiment 135, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 68, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; an amino acid sequence of SEQ ID NO: 106, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 144, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 138. The template RNA or system of embodiment 135 or the system of 136 or 137, wherein the PBS has a nucleotide sequence of SEQ ID NO: 334 or SEQ ID NO: 372, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 139. The template RNA or system of any one of embodiments 1-25, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 259, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 297, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 140. The system of embodiment 139, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 69, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. Page 25 of 356 12806819v1Attorney Docket No.: 2017469-0045 141. The system of embodiment 139, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 69, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 107, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 142. The template RNA or system of embodiment 139 or the system of 140 or 141, wherein the PBS has a nucleotide sequence of SEQ ID NO: 335 or SEQ ID NO: 373, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 143. The template RNA or system of any one of embodiments 1-25, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 260, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 298, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 144. The system of embodiment 143, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 70, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 145. The template RNA or system of embodiment 143 or the system of 144, wherein the PBS has a nucleotide sequence of SEQ ID NO: 336 or SEQ ID NO: 374, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 146. The template RNA or system of any one of embodiments 1-25, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 261, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 299, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. Page 26 of 356 12806819v1Attorney Docket No.: 2017469-0045 147. The system of embodiment 146, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 71, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 148. The system of embodiment 146, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 71, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 109, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 149. The template RNA or system of embodiment 146 or the system of 147 or 148, wherein the PBS has a nucleotide sequence of SEQ ID NO: 337 or SEQ ID NO: 375, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 150. The template RNA or system of any one of embodiments 1-25, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 262, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 300, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 151. The system of embodiment 150, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 72, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 152. The system of embodiment 150, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 72, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or Page 27 of 356 12806819v1Attorney Docket No.: 2017469-0045 an amino acid sequence of SEQ ID NO: 110, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 153. The template RNA or system of embodiment 150 or the system of 151 or 152, wherein the PBS has a nucleotide sequence of SEQ ID NO: 338 or SEQ ID NO: 376, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 154. The template RNA or system of any one of embodiments 1-25, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 263, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 301, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 155. The system of embodiment 154, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 73, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 156. The template RNA or system of embodiment 154 or the system of 155, wherein the PBS has a nucleotide sequence of SEQ ID NO: 339 or SEQ ID NO: 377, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 157. The template RNA or system of any one of embodiments 1-25, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 264, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 302, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 158. The system of embodiment 157, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 74, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. Page 28 of 356 12806819v1Attorney Docket No.: 2017469-0045 159. The system of embodiment 157, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 74, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; an amino acid sequence of SEQ ID NO: 112, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 150, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 160. The template RNA or system of embodiment 157 or the system of 158 or 159, wherein the PBS has a nucleotide sequence of SEQ ID NO: 340 or SEQ ID NO: 378, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 161. The template RNA or system of any one of embodiments 1-25, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 265, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 303, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 162. The system of embodiment 161, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 75, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 163. The template RNA or system of embodiment 161 or the system of 162, wherein the PBS has a nucleotide sequence of SEQ ID NO: 341 or SEQ ID NO: 379, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 164. The template RNA or system of any one of embodiments 1-25, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 266, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and Page 29 of 356 12806819v1Attorney Docket No.: 2017469-0045 the 3’ LTR has a nucleotide sequence of SEQ ID NO: 304, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 165. The system of embodiment 164, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 76, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 166. The template RNA or system of embodiment 164 or the system of 165, wherein the PBS has a nucleotide sequence of SEQ ID NO: 342 or SEQ ID NO: 380, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 167. The system or polypeptide driver of any one of the preceding embodiments, wherein the polypeptide driver comprises a gag domain. 168. The system of any one of the preceding embodiments, wherein the polypeptide driver comprises a at least two gag domains. 169. The system of any one of the preceding embodiments, wherein the polypeptide driver comprises a pro domain. 170. The system of any one of the preceding embodiments, wherein the polypeptide driver comprises a pol domain. 171. The system of any one of the preceding embodiments, wherein the polypeptide driver comprises at least two pol domains. 172. A template RNA comprising: a 5’ long terminal repeat (5’ LTR) having a sequence according to column 3 of Table J, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; Page 30 of 356 12806819v1Attorney Docket No.: 2017469-0045 a 3’ long terminal repeat (3’ LTR) having a sequence according to column 5 of the same row of Table J as the 5’ LTR, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; a heterologous object sequence encoding a therapeutic effector, positioned between the 5’ LTR and the 3’ LTR, and a primer binding site (PBS). 173. A system for modifying DNA comprising: a) a template RNA of embodiment 172, or a DNA molecule encoding the template RNA; and b) a polypeptide driver having an amino acid sequence according to Table L that corresponds to the 5’ LTR and 3’ LTR, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; or a nucleic acid molecule or a plurality of nucleic acid molecules encoding the polypeptide driver. 174. The system of embodiment 173, wherein the polypeptide driver further comprises an amino acid sequence according to Table M that corresponds to the 5’ LTR and 3’ LTR, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 175. The system of embodiment 174, wherein the polypeptide driver further comprises an amino acid sequence according to Table N that corresponds to the 5’ LTR and 3’ LTR, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 176. The system of embodiment 175, wherein the polypeptide driver further comprises an amino acid sequence according to Table O that corresponds to the 5’ LTR and 3’ LTR, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. Page 31 of 356 12806819v1Attorney Docket No.: 2017469-0045 177. The system of embodiment 176, wherein the polypeptide driver further comprises an amino acid sequence according to Table P that corresponds to the 5’ LTR and 3’ LTR, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 178. The system of any one of embodiments 173-177, wherein the template RNA and the nucleic acid encoding the polypeptide driver are separate nucleic acids. 179. The system of any one of embodiments 173-177, wherein the template RNA and the nucleic acid encoding the polypeptide driver are present in the same nucleic acid. 180. A polypeptide driver having an amino acid sequence according to Table L, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 181. The polypeptide driver of embodiment 180, which further comprises an amino acid sequence according to Table M that corresponds to the sequence of Table L, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 182. The polypeptide driver of embodiment 180 or 181, which further comprises an amino acid sequence according to Table N that corresponds to the sequence of Table L, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 183. The polypeptide driver of any one of embodiments 180-182, which further comprises an amino acid sequence according to Table O that corresponds to the sequence of Table L, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 184. The polypeptide driver of any one of embodiments 180-183, which further comprises an amino acid sequence according to Table P that corresponds to the sequence of Table L, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. Page 32 of 356 12806819v1Attorney Docket No.: 2017469-0045 185. A polypeptide driver having an amino acid sequence according to Table M, N, O, or P, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 186. The system or polypeptide driver of any one of embodiments 174-185, wherein the sequence of Table L and the sequence of Table M are in separate polypeptide chains. 187. The system or polypeptide driver of any one of embodiments 174-185, wherein the sequence of Table L and the sequence of Table M are fused in a single polypeptide chain. 188. The system or polypeptide driver of any one of embodiments 175-185, wherein the sequence of Table L, the sequence of Table M, and the sequence of Table N are in separate polypeptide chains. 189. The system or polypeptide driver of any one of embodiments 175-185, wherein the sequence of Table L, the sequence of Table M, and the sequence of Table N are fused in a single polypeptide chain. 190. The system or polypeptide driver of any one of embodiments 176-185, wherein the sequence of Table L, the sequence of Table M, the sequence of Table N, and the sequence of Table O are in separate polypeptide chains. 191. The system or polypeptide driver of any one of embodiments 176-185, wherein the sequence of Table L, the sequence of Table M, the sequence of Table N, and the sequence of Table O are fused in a single polypeptide chain. 192. The system or polypeptide driver of embodiments 177-185, wherein the sequence of Table L, the sequence of Table M, the sequence of Table N, the sequence of Table O, and the sequence of Table P are in separate polypeptide chains. Page 33 of 356 12806819v1Attorney Docket No.: 2017469-0045 193. The system or polypeptide driver of any one of embodiments 177-185, wherein the sequence of Table L, the sequence of Table M, the sequence of Table N, the sequence of Table O, and the sequence of Table P are fused in a single polypeptide chain. 194. The template RNA or system of any one of the preceding embodiments, wherein the PBS is situated between the 5’ LTR and the heterologous object sequence. 195. The template RNA or system of any one of the preceding embodiments, wherein the PBS has a sequence according to Table K, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 196. The template RNA or system of any one of the preceding embodiments, wherein the PBS has a sequence according to Table Z, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 197. A nucleic acid molecule or a plurality of nucleic acid molecules (e.g., mRNA) encoding the polypeptide driver of any one of embodiments 180-193. 198. The template RNA or system of any one of embodiments 173-196, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 410, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 439, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 199. The system of embodiment 198, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 555, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 200. The template RNA or system of embodiment 198, wherein the PBS has a nucleotide sequence of SEQ ID NO: 468 or SEQ ID NO: 497, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. Page 34 of 356 12806819v1Attorney Docket No.: 2017469-0045 201. The template RNA or system of any one of embodiments 172-196, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 411, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 440, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 202. The system of embodiment 201, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 556, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 203. The template RNA or system of embodiment 201 or the system of 202, wherein the PBS has a nucleotide sequence of SEQ ID NO: 469 or SEQ ID NO: 498, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 204. The template RNA or system of any one of embodiments 172-196, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 412, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 441, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 205. The system of embodiment 204, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 557, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 206. The system of embodiment 204, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 557, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; an amino acid sequence of SEQ ID NO: 586, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or Page 35 of 356 12806819v1Attorney Docket No.: 2017469-0045 an amino acid sequence of SEQ ID NO: 615, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 207. The template RNA or system of embodiment 204 or the system of 205 or 206, wherein the PBS has a nucleotide sequence of SEQ ID NO: 470 or SEQ ID NO: 499, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 208. The template RNA or system of any one of embodiments 172-196, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 413, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 442, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 209. The system of embodiment 208, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 558, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 210. The system of embodiment 208, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 558, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 587, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 211. The template RNA or system of embodiment 208 or the system of 209 or 210, wherein the PBS has a nucleotide sequence of SEQ ID NO: 471 or SEQ ID NO: 500, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 212. The template RNA or system of any one of embodiments 172-196, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 414, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and Page 36 of 356 12806819v1Attorney Docket No.: 2017469-0045 the 3’ LTR has a nucleotide sequence of SEQ ID NO: 443, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 213. The system of embodiment 212, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 559, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 214. The system of embodiment 212, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 559, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; an amino acid sequence of SEQ ID NO: 588, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; an amino acid sequence of SEQ ID NO: 617, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 646, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 215. The template RNA or system of embodiment 212 or the system of 213 or 214, wherein the PBS has a nucleotide sequence of SEQ ID NO: 472 or SEQ ID NO: 501, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 216. The template RNA or system of any one of embodiments 172-196, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 415, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 444, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 217. The system of embodiment 216, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 560, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. Page 37 of 356 12806819v1Attorney Docket No.: 2017469-0045 218. The system of embodiment 216, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 560, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; an amino acid sequence of SEQ ID NO: 589, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; an amino acid sequence of SEQ ID NO: 618, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 647, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 219. The template RNA or system of embodiment 216 or the system of 217 or 218, wherein the PBS has a nucleotide sequence of SEQ ID NO: 473 or SEQ ID NO: 502, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 220. The template RNA or system of any one of embodiments 172-196, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 416, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 445, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 221. The system of embodiment 220, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 561, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 222. The system of embodiment 220, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 561, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or Page 38 of 356 12806819v1Attorney Docket No.: 2017469-0045 an amino acid sequence of SEQ ID NO: 590, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 223. The template RNA or system of embodiment 220 or the system of 221 or 222, wherein the PBS has a nucleotide sequence of SEQ ID NO: 474 or SEQ ID NO: 503, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 224. The template RNA or system of any one of embodiments 172-196, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 417, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 446, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 225. The system of embodiment 224, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 562, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 226. The system of embodiment 224, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 562, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; an amino acid sequence of SEQ ID NO: 591, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; an amino acid sequence of SEQ ID NO: 620, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; an amino acid sequence of SEQ ID NO: 649, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 678, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. Page 39 of 356 12806819v1Attorney Docket No.: 2017469-0045 227. The template RNA or system of embodiment 224 or the system of 225 or 226, wherein the PBS has a nucleotide sequence of SEQ ID NO: 475 or SEQ ID NO: 504, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 228. The template RNA or system of any one of embodiments 172-196, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 418, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 447, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 229. The system of embodiment 228, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 563, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 230. The system of embodiment 228, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 563, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 592, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 231. The template RNA or system of embodiment 228 or the system of 229 or 230, wherein the PBS has a nucleotide sequence of SEQ ID NO: 476 or SEQ ID NO: 505, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 232. The template RNA or system of any one of embodiments 172-196, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 419, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 448, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. Page 40 of 356 12806819v1Attorney Docket No.: 2017469-0045 233. The system of embodiment 232, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 564, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 234. The system of embodiment 232, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 564, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 593, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 235. The template RNA or system of embodiment 232 or the system of 233 or 234, wherein the PBS has a nucleotide sequence of SEQ ID NO: 477 or SEQ ID NO: 506, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 236. The template RNA or system of any one of embodiments 172-196, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 420, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 449, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 237. The system of embodiment 236, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 565, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 238. The system of embodiment 236, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 565, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; an amino acid sequence of SEQ ID NO: 594, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or Page 41 of 356 12806819v1Attorney Docket No.: 2017469-0045 an amino acid sequence of SEQ ID NO: 623, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 239. The template RNA or system of embodiment 236 or the system of 237 or 238, wherein the PBS has a nucleotide sequence of SEQ ID NO: 478 or SEQ ID NO: 507, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 240. The template RNA or system of any one of embodiments 172-196, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 421, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 450, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 241. The system of embodiment 240, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 566, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 242. The system of embodiment 240, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 566, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; an amino acid sequence of SEQ ID NO: 595, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 624, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 243. The template RNA or system of embodiment 240 or the system of 241 or 242, wherein the PBS has a nucleotide sequence of SEQ ID NO: 479 or SEQ ID NO: 508, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. Page 42 of 356 12806819v1Attorney Docket No.: 2017469-0045 244. The template RNA or system of any one of embodiments 172-196, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 422, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 451, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 245. The system of embodiment 244, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 567, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 246. The system of embodiment 244, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 567, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; an amino acid sequence of SEQ ID NO: 596, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 625, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 247. The template RNA or system of embodiment 244 or the system of 245 or 246, wherein the PBS has a nucleotide sequence of SEQ ID NO: 480 or SEQ ID NO: 509, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 248. The template RNA or system of any one of embodiments 172-196, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 423, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 452, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. Page 43 of 356 12806819v1Attorney Docket No.: 2017469-0045 249. The system of embodiment 248, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 568, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 250. The system of embodiment 248, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 568, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 597, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 251. The template RNA or system of embodiment 248 or the system of 249 or 250, wherein the PBS has a nucleotide sequence of SEQ ID NO: 481 or SEQ ID NO: 510, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 252. The template RNA or system of any one of embodiments 172-196, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 424, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 453, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 253. The system of embodiment 252, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 569, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 254. The system of embodiment 252, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 569, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 598, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. Page 44 of 356 12806819v1Attorney Docket No.: 2017469-0045 255. The template RNA or system of embodiment 252 or the system of 253 or 254, wherein the PBS has a nucleotide sequence of SEQ ID NO: 482 or SEQ ID NO: 511, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 256. The template RNA or system of any one of embodiments 172-196, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 425, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 454, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 257. The system of embodiment 256, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 570, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 258. The system of embodiment 256, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 570, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 599, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 259. The template RNA or system of embodiment 256 or the system of 257 or 258, wherein the PBS has a nucleotide sequence of SEQ ID NO: 483 or SEQ ID NO: 512, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 260. The template RNA or system of any one of embodiments 172-196, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 426, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 455, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. Page 45 of 356 12806819v1Attorney Docket No.: 2017469-0045 261. The system of embodiment 260, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 571, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 262. The system of embodiment 260, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 571, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 600, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 263. The template RNA or system of embodiment 260 or the system of 261 or 262, wherein the PBS has a nucleotide sequence of SEQ ID NO: 484 or SEQ ID NO: 513, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 264. The template RNA or system of any one of embodiments 172-196, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 427, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 456, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 265. The system of embodiment 264, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 572, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 266. The system of embodiment 264, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 572, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; Page 46 of 356 12806819v1Attorney Docket No.: 2017469-0045 an amino acid sequence of SEQ ID NO: 601, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 630, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 267. The template RNA or system of embodiment 264 or the system of 265 or 266, wherein the PBS has a nucleotide sequence of SEQ ID NO: 485 or SEQ ID NO: 514, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 268. The template RNA or system of any one of embodiments 172-196, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 428, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 457, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 269. The system of embodiment 268, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 573, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 270. The system of embodiment 268, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 573, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 602, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 271. The template RNA or system of embodiment 268 or the system of 269 or 270, wherein the PBS has a nucleotide sequence of SEQ ID NO: 486 or SEQ ID NO: 515, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. Page 47 of 356 12806819v1Attorney Docket No.: 2017469-0045 272. The template RNA or system of any one of embodiments 172-196, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 429, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 458, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 273. The system of embodiment 272, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 574, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 274. The system of embodiment 272, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 574, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 603, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 275. The template RNA or system of embodiment 272 or the system of 273 or 274, wherein the PBS has a nucleotide sequence of SEQ ID NO: 487 or SEQ ID NO: 516, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 276. The template RNA or system of any one of embodiments 172-196, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 430, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 459, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 277. The system of embodiment 276, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 575, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. Page 48 of 356 12806819v1Attorney Docket No.: 2017469-0045 278. The system of embodiment 276, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 575, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 604, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 279. The template RNA or system of embodiment 276 or the system of 277 or 278, wherein the PBS has a nucleotide sequence of SEQ ID NO: 488 or SEQ ID NO: 517, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 280. The template RNA or system of any one of embodiments 172-196, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 431, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 460, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 281. The system of embodiment 280, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 576, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 282. The system of embodiment 280, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 576, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 605, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 283. The template RNA or system of embodiment 280 or the system of 281 or 282, wherein the PBS has a nucleotide sequence of SEQ ID NO: 489 or SEQ ID NO: 518, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. Page 49 of 356 12806819v1Attorney Docket No.: 2017469-0045 284. The template RNA or system of any one of embodiments 172-196, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 432, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 461, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 285. The system of embodiment 284, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 577, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 286. The system of embodiment 284, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 577, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; an amino acid sequence of SEQ ID NO: 606, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 635, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 287. The template RNA or system of embodiment 284 or the system of 285 or 286, wherein the PBS has a nucleotide sequence of SEQ ID NO: 490 or SEQ ID NO: 519, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 288. The template RNA or system of any one of embodiments 172-196, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 433, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 462, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. Page 50 of 356 12806819v1Attorney Docket No.: 2017469-0045 289. The system of embodiment 288, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 578, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 290. The system of embodiment 288, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 578, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto an amino acid sequence of SEQ ID NO: 607, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 636, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 291. The template RNA or system of embodiment 288 or the system of 289 or 290, wherein the PBS has a nucleotide sequence of SEQ ID NO: 491 or SEQ ID NO: 520, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 292. The template RNA or system of any one of embodiments 172-196, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 434, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 463, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 293. The system of embodiment 292, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 579, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 294. The system of embodiment 292, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 579, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or Page 51 of 356 12806819v1Attorney Docket No.: 2017469-0045 an amino acid sequence of SEQ ID NO: 608, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 295. The template RNA or system of embodiment 292 or the system of 293 or 294, wherein the PBS has a nucleotide sequence of SEQ ID NO: 492 or SEQ ID NO: 521, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 296. The template RNA or system of any one of embodiments 172-196, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 435, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 464, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 297. The system of embodiment 296, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 580, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 298. The system of embodiment 296, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 580, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 609, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 299. The template RNA or system of embodiment 296 or the system of 297 or 298, wherein the PBS has a nucleotide sequence of SEQ ID NO: 493 or SEQ ID NO: 522, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 300. The template RNA or system of any one of embodiments 172-196, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 436, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and Page 52 of 356 12806819v1Attorney Docket No.: 2017469-0045 the 3’ LTR has a nucleotide sequence of SEQ ID NO: 465, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 301. The system of embodiment 300, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 581, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 302. The system of embodiment 300, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 581, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 610, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 303. The template RNA or system of embodiment 300 or the system of 301 or 302, wherein the PBS has a nucleotide sequence of SEQ ID NO: 494 or SEQ ID NO: 523, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 304. The template RNA or system of any one of embodiments 172-196, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 437, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 466, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 305. The system of embodiment 304, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 582, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 306. The template RNA or system of embodiment 304 or the system of 305, wherein the PBS has a nucleotide sequence of SEQ ID NO: 495 or SEQ ID NO: 524, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. Page 53 of 356 12806819v1Attorney Docket No.: 2017469-0045 307. The template RNA or system of any one of embodiments 172-196, wherein: the 5’ LTR has a nucleotide sequence of SEQ ID NO: 438, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and the 3’ LTR has a nucleotide sequence of SEQ ID NO: 467, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 308. The system of embodiment 307, wherein the driver polypeptide comprises an amino acid sequence of SEQ ID NO: 583, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. 309. The system of embodiment 307, wherein the driver polypeptide comprises (in a single polypeptide chain or a plurality of polypeptide chains): an amino acid sequence of SEQ ID NO: 583, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or an amino acid sequence of SEQ ID NO: 612. 310. The template RNA or system of embodiment 307 or the system of 308 or 309, wherein the PBS has a nucleotide sequence of SEQ ID NO: 496 or SEQ ID NO: 525, or a sequence with no more than 1, 2, or 3 substitutions relative thereto. 311. The system or polypeptide driver of any one of the preceding embodiments, wherein the polypeptide driver comprises a gag domain. 312. The system of any one of the preceding embodiments, wherein the polypeptide driver comprises a at least two gag domains. 313. The system of any one of the preceding embodiments, wherein the polypeptide driver comprises a pro domain. Page 54 of 356 12806819v1Attorney Docket No.: 2017469-0045 314. The system of any one of the preceding embodiments, wherein the polypeptide driver comprises a pol domain. 315. The system of any one of the preceding embodiments, wherein the polypeptide driver comprises at least two pol domains. 316. The system of any one of the preceding embodiments, wherein the system is substantially free of virus. 317. The system of any one of the preceding embodiments, wherein the system is substantially free of cells. 318. A nucleic acid encoding the polypeptide driver of any one of the preceding embodiments. 319. The nucleic acid of embodiment 318, wherein the nucleic acid encoding the polypeptide driver is an mRNA. 320. The nucleic acid of embodiment 318 or 319, wherein the nucleic acid encoding the driver polypeptide comprises one or more non-canonical or modified ribonucleotides. 321. The system or the template RNA of any one of the preceding embodiments, wherein the template RNA comprises one or more non-canonical or modified ribonucleotides. 322. A DNA molecule encoding the template RNA of any one of the preceding embodiments. 323. A pharmaceutical composition comprising the template RNA or the system of any one of the preceding embodiments. 324. The system, polypeptide driver, or method of any one of the preceding embodiments, wherein the system, nucleic acid molecule, polypeptide, and / or DNA encoding the same, is formulated as a lipid nanoparticle (LNP). Page 55 of 356 12806819v1Attorney Docket No.: 2017469-0045 325. A cell comprising the system of any one of the preceding embodiments. 326. A cell comprising the template RNA of any one of the preceding embodiments. 327. A cell comprising the polypeptide driver of any one of the preceding embodiments. 328. A method of delivering a heterologous object sequence to a target cell, comprising: introducing into the target cell (e.g., contacting the target cell with) a system of any one of the preceding embodiments, and incubating the target cell under conditions suitable for production of the template DNA. Definitions

[0005] About, approximately: “About” or “approximately” as the terms are used herein applied to one or more values of interest, refer to a value that is similar to a stated reference value. In certain embodiments, the term “approximately” or “about” refers to a range of values that fall within 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).

[0006] Domain: The term “domain” as used herein refers to a structure of a biomolecule that contributes to a specified function of the biomolecule. A domain may comprise a contiguous region (e.g., a contiguous sequence) or distinct, non-contiguous regions (e.g., non-contiguous sequences) of a biomolecule. Examples of protein domains include, but are not limited to, a nuclear localization sequence, a recombinase domain, a retroviral (e.g., endogenous retroviral) structural polypeptide domain, a retroviral (e.g., endogenous retroviral) reverse transcriptase polypeptide domain, a retrotransposon structural polypeptide domain, a retrotransposon reverse transcriptase polypeptide domain, a DNA recognition domain (e.g., that binds to or is capable of binding to a recognition site, e.g. as described herein), a recombinase N-terminal domain (also called a catalytic domain), a C-terminal zinc ribbon domain. In some embodiments the zinc ribbon domain further comprises a coiled-coiled motif. In some embodiments, the recombinase Page 56 of 356 12806819v1Attorney Docket No.: 2017469-0045 domain and the zinc ribbon domain are collectively referred to as the C-terminal domain. In some embodiments the N-terminal domain is linked to the C-terminal domain by an αE linker or helix. In some embodiments the N-terminal domain is between 50 and 250 amino acids, or 100- 200 amino acids, or 130 - 170 amino acids, e.g., about 150 amino acids. In some embodiments the C-terminal domain is 200-800 amino acids, or 300-500 amino acids. In some embodiments the recombinase domain is between 50 and 150 amino acids. In some embodiments the zinc ribbon domain is between 30 and 100 amino acids; an example of a domain of a nucleic acid is a regulatory domain, such as a transcription factor binding domain, a recognition sequence, an arm of a recognition sequence (e.g. a 5’ or 3’ arm), a core sequence, or an object sequence (e.g., a heterologous object sequence).

[0007] Exogenous: As used herein, the term exogenous, when used with reference to a biomolecule (such as a nucleic acid sequence or polypeptide) means that the biomolecule was introduced into a host genome, cell or organism by the hand of man. For example, a nucleic acid that is as added into an existing genome, cell, tissue or subject using recombinant DNA techniques or other methods is exogenous to the existing nucleic acid sequence, cell, tissue or subject.

[0008] Heterologous: The term heterologous, when used to describe a first element in reference to a second element means that the first element and second element do not exist in nature disposed as described. For example, a heterologous polypeptide, nucleic acid molecule, construct or sequence refers to (a) a polypeptide, nucleic acid molecule or portion of a polypeptide or nucleic acid molecule sequence that is not native to a cell in which it is expressed, (b) a polypeptide or nucleic acid molecule or portion of a polypeptide or nucleic acid molecule that has been altered or mutated relative to its native state, or (c) a polypeptide or nucleic acid molecule with an altered expression as compared to the native expression levels under similar conditions. For example, a heterologous regulatory sequence (e.g., promoter, enhancer) may be used to regulate expression of a gene or a nucleic acid molecule in a way that is different than the gene or a nucleic acid molecule is normally expressed in nature. In another example, a heterologous domain of a polypeptide or nucleic acid sequence (e.g., a DNA binding domain of a polypeptide or nucleic acid encoding a DNA binding domain of a polypeptide) may be disposed relative to other domains or may be a different sequence or from a different source, relative to other domains or portions of a polypeptide or its encoding nucleic acid. In certain embodiments, Page 57 of 356 12806819v1Attorney Docket No.: 2017469-0045 a heterologous nucleic acid molecule may exist in a native host cell genome, but may have an altered expression level or have a different sequence or both. In other embodiments, heterologous nucleic acid molecules may not be endogenous to a host cell or host genome but instead may have been introduced into a host cell by transformation (e.g., transfection, electroporation), wherein the added molecule may integrate into the host genome or can exist as extra- chromosomal genetic material either transiently (e.g., mRNA) or semi-stably for more than one generation (e.g., episomal viral vector, plasmid or other self-replicating vector). In some embodiments, a domain is heterologous relative to another domain, if the first domain is not naturally comprised in the same polypeptide as the other domain (e.g., a fusion between two domains of different proteins from the same organism).

[0009] Long Terminal Repeat: The term “long terminal repeat” (LTR), as used herein, refers to a nucleic acid sequence, which in a wild-type context are found in pairs (which may be identical or have sequence similarity) that flank a retrovirus or an LTR retrotransposon. The term “LTR” also encompasses variants and fragments of a wild-type LTR which are functional for integration of a region of the nucleic acid molecule comprising the LTR into a target DNA molecule in the presence of factors from the retrovirus or LTR retrotransposon. An LTR is typically located at or near one end (e.g., the 5’ end or the 3’ end) of a template DNA or RNA, e.g., as described herein. In some instances, an LTR participates in integration of a heterologous object sequence comprised in the template DNA or RNA into a target DNA molecule (e.g., a genomic DNA). In some instances, the LTR, or a fragment thereof, is integrated into the target DNA molecule. In some instances, the LTR is not integrated into the target DNA molecule. In some instances, a 5’ LTR of a template DNA or RNA (e.g., as described herein) has at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a 3’ LTR sequence of the template DNA or RNA. In some instances, an LTR of a system or composition described herein has at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to an LTR sequence of a naturally occurring retrovirus (e.g., endogenous retrovirus) or LTR retrotransposon. In some instances, an LTR of a system or composition described herein has at least one modification (e.g., an addition, substitution, or deletion) relative to an LTR sequence of a naturally occurring retrovirus (e.g., endogenous retrovirus) or LTR retrotransposon. In some embodiments, an LTR has promoter and / or enhancer activity. Page 58 of 356 12806819v1Attorney Docket No.: 2017469-0045

[0010] Mutation or Mutated: The term “mutated” when applied to nucleic acid sequences means that nucleotides in a nucleic acid sequence may be inserted, deleted or changed compared to a reference (e.g., native) nucleic acid sequence. A single alteration may be made at a locus (a point mutation) or multiple nucleotides may be inserted, deleted or changed at a single locus. In addition, one or more alterations may be made at any number of loci within a nucleic acid sequence. A nucleic acid sequence may be mutated by any method known in the art. In some embodiments a mutation occurs naturally. In some embodiments a desired mutation can be produced by any suitable method.

[0011] Nucleic acid molecule: Nucleic acid molecule refers to both RNA and DNA molecules including, without limitation, cDNA, genomic DNA and mRNA, and also includes synthetic nucleic acid molecules, such as those that are chemically synthesized or recombinantly produced, such as RNA templates, as described herein. The nucleic acid molecule can be double-stranded or single-stranded, circular or linear. If single-stranded, the nucleic acid molecule can be the sense strand or the antisense strand. Unless otherwise indicated, and as an example for all sequences described herein under the general format “SEQ. ID NO:,” “nucleic acid comprising SEQ. ID NO:1” refers to a nucleic acid, at least a portion which has either (i) the sequence of SEQ. ID NO:1, or (ii) a sequence complementary to SEQ. ID NO:1. The choice between the two is dictated by the context in which SEQ. ID NO:1 is used. For instance, if the nucleic acid is used as a probe, the choice between the two is dictated by the requirement that the probe be complementary to the desired target. Nucleic acid sequences of the present disclosure may be modified chemically or biochemically or may contain non-natural or derivatized nucleotide bases, as will be readily appreciated by those of skill in the art. Such modifications include, for example, labels, methylation, substitution of one or more naturally occurring nucleotides with an analog, inter-nucleotide modifications such as uncharged linkages (for example, methyl phosphonates, phosphotriesters, phosphoramidates, carbamates, etc.), charged linkages (for example, phosphorothioates, phosphorodithioates, etc.), pendant moieties, (for example, polypeptides), intercalators (for example, acridine, psoralen, etc.), chelators, alkylators, and modified linkages (for example, alpha anomeric nucleic acids, etc.). Also included are synthetic molecules that mimic polynucleotides in their ability to bind to a designated sequence via hydrogen bonding and other chemical interactions. Such molecules are known in the art and include, for example, those in which peptide linkages substitute for phosphate linkages in the Page 59 of 356 12806819v1Attorney Docket No.: 2017469-0045 backbone of a molecule. Other modifications can include, for example, analogs in which the ribose ring contains a bridging moiety or other structure such as modifications found in “locked” nucleic acids.

[0012] Gene expression unit: a gene expression unit is a nucleic acid sequence comprising at least one regulatory nucleic acid sequence operably linked to at least one effector sequence. A first nucleic acid sequence is operably linked with a second nucleic acid sequence when the first nucleic acid sequence is placed in a functional relationship with the second nucleic acid sequence. For instance, a promoter or enhancer is operably linked to a coding sequence if the promoter or enhancer affects the transcription or expression of the coding sequence. Operably linked DNA sequences may be contiguous or non-contiguous. Where necessary to join two protein-coding regions, operably linked sequences may be in the same reading frame.

[0013] Host: The terms host genome or host cell, as used herein, refer to a cell and / or its genome into which protein and / or genetic material has been introduced. It should be understood that such terms are intended to refer not only to the particular subject cell and / or genome, but to the progeny of such a cell and / or the genome of the progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term “host cell” as used herein. A host genome or host cell may be an isolated cell or cell line grown in culture, or genomic material isolated from such a cell or cell line or may be a host cell or host genome which composing living tissue or an organism. In some instances, a host cell may be an animal cell or a plant cell, e.g., as described herein. In certain instances, a host cell may be a bovine cell, horse cell, pig cell, goat cell, sheep cell, chicken cell, or turkey cell. In certain instances, a host cell may be a corn cell, soy cell, wheat cell, or rice cell.

[0014] Introducing: As used herein, the term “introducing”, in the context of introducing an agent into a call, refers to causing the agent to be comprised by the cell. For example, the cell may be contacted with the agent in a way that allows the agent to pass through the cell membrane to enter the cell. Alternatively, the agent can be introduced into the cell by causing the cell to produce the agent. For instance, an agent that is a polypeptide can be introduced into the cell by contacting the cell with a nucleic acid encoding the polypeptide, under conditions that the nucleic acid enters the cell and is translated to produce the polypeptide. Page 60 of 356 12806819v1Attorney Docket No.: 2017469-0045

[0015] Contacting: As used herein, the term “contacting”, in the context of contacting a cell with an agent, comprises placing the agent at a location that allows the agent to come into physical contact with the cell. Physical contact with the cell includes, e.g., binding to the cell surface or being internalized into the cell. In some embodiments, e.g., ex vivo, contacting a cell with an agent comprises introducing the agent into media, wherein the media is in contact with the cell. In some embodiments, e.g., in vivo, contacting a cell with an agent comprises administering the agent to a subject comprising the cell, under conditions that allow the agent to come into physical contact with the cell.

[0016] Object sequence: As used herein, the term object sequence refers to a nucleic acid segment that can be desirably inserted into a target nucleic acid molecule, e.g., by a recombinase polypeptide, e.g., as described herein. In some embodiments, a template RNA or template DNA comprises a DNA recognition sequence and an object sequence that is heterologous to the DNA recognition sequence and / or the remainder of the template RNA or template DNA, generally referred to herein as a “heterologous object sequence.” An object sequence may, in some instances, be heterologous relative to the nucleic acid molecule into which it is inserted (e.g., a target DNA molecule, e.g., as described herein). In some instances, an object sequence comprises a nucleic acid sequence encoding a gene (e.g., a eukaryotic gene, e.g., a mammalian gene, e.g., a human gene) or other cargo of interest (e.g., a sequence encoding a functional RNA, e.g., an siRNA or miRNA), e.g., as described herein. In certain instances, the gene encodes a polypeptide (e.g., a blood factor or enzyme). In some instances, an object sequence comprises one or more of a nucleic acid sequence encoding a selectable marker (e.g., an auxotrophic marker or an antibiotic marker), and / or a nucleic acid control element (e.g., a promoter, enhancer, silencer, or insulator).

[0017] Polypeptide driver: As used herein, the term “polypeptide driver” refers to a polypeptide or a plurality of polypeptides that can carry out retrotransposition of a compatible template RNA. In some embodiments, the polypeptide driver comprises a single polypeptide having multiple domains, for example, two or more domains chosen from GAG, PRO, and POL. In some embodiments, the polypeptide driver comprises a plurality of separate polypeptides, wherein each polypeptide in the plurality comprises one or more domains chosen from GAG, PRO, and POL. In some embodiments, the polypeptide driver is encoded by overlapping ORFs. Page 61 of 356 12806819v1Attorney Docket No.: 2017469-0045

[0018] Structural polypeptide domain: As used herein, the term “structural polypeptide domain” refers to a polypeptide domain that can form part of a proteinaceous exterior (e.g., a viral capsid) encapsulating a nucleic acid (e.g., a template RNA, e.g., as described herein). Retroviral env is not a structural polypeptide domain, as the term is used herein. In some instances, a structural polypeptide domain is encoded by a viral gene (e.g., a retroviral gag gene). In some instances, a structural polypeptide domain comprises a capsid protein (e.g., a CA protein and / or an NC protein, e.g., encoded by a retroviral gag gene), or a functional fragment thereof. In some instances, a structural polypeptide domain comprises a matrix protein (e.g., a MA protein, e.g., encoded by a retroviral gag gene), or a functional fragment thereof. In some instances, a structural polypeptide domain comprises a domain encoded by a retroviral gag (e.g., an endogenous retroviral gag). In some embodiments, a structural polypeptide domain comprises one or more mutations (e.g., point mutations, additions, substitutions, or deletions) relative to the amino acid sequence of a corresponding wild-type protein (e.g., a wild-type retroviral gag, CA, NC, or MA protein). In some embodiments, a structural polypeptide domain is part of a polyprotein or a fusion protein. In some embodiments, a structural polypeptide domain is not part of a polyprotein or a fusion protein.

[0019] Reverse transcriptase domain: As used herein, the term “reverse transcriptase domain” refers to a polypeptide domain capable of producing complementary DNA from a template RNA (e.g., as described herein). In some instances, a reverse transcriptase domain comprises a viral (e.g., retroviral, e.g., endogenous retroviral) reverse transcriptase, or a functional fragment thereof. In some instances, a reverse transcriptase domain produces complementary DNA from a template RNA via a primer (e.g., a tRNA primer, e.g., a lysyl tRNA primer). In some instances, a reverse transcriptase domain produces a double stranded template DNA (e.g., as described herein) from the template RNA. In some instances, a reverse transcriptase domain is encoded by a viral (e.g., retroviral, e.g., endogenous retroviral) pol gene. In some instances, a reverse transcriptase domain is encoded by a pol gene that also encodes a viral (e.g., retroviral, e.g., endogenous retroviral) integrase (IN). In some instances, a reverse transcriptase domain is encoded by a pol gene that also encodes a viral (e.g., retroviral, e.g., endogenous retroviral) protease (PR) and / or dTUPase (DU). In some embodiments, a reverse transcriptase polypeptide domain comprises one or more mutations (e.g., point mutations, additions, substitutions, or deletions) relative to the amino acid sequence of a corresponding Page 62 of 356 12806819v1Attorney Docket No.: 2017469-0045 wild-type protein (e.g., a wild-type retroviral pol, IN, PR, or DU protein). In some embodiments, a reverse transcriptase domain is part of a polyprotein or a fusion protein. In some embodiments, a reverse transcriptase domain is not part of a polyprotein or a fusion protein. In some embodiments, the reverse transcriptase domain comprises RNaseH activity. In some embodiments, a functional reverse transcriptase comprises a single protein subunit, e.g., is monomeric. In some embodiments, a functional reverse transcriptase comprises at least two subunits, e.g., is dimeric. In some embodiments, the reverse transcriptase domain is less active (or inactive) in monomeric form compared to in dimeric form. In some embodiments, a dimeric reverse transcriptase comprises two identical subunits. In some embodiments, a dimeric reverse transcriptase comprises different subunits, e.g., a p51 and a p66 subunit. In some embodiments, a reverse transcriptase comprises at least three subunits, e.g., two p51 subunits and at least one p15 subunit. In some embodiments, a reverse transcriptase comprises an RNase H domain. In some embodiments, a reverse transcriptase comprises an inactivated RNase H domain. In some embodiments, a reverse transcriptase does not comprise an RNase H domain.

[0020] LTR retrotransposon: As used herein, the term “LTR retrotransposon” in the context of a domain (e.g., LTR retrotransposon structural polypeptide domain or LTR retrotransposon reverse transcriptase polypeptide domain) refers to a polypeptide domain having sequence similarity to a corresponding domain from a wild-type LTR retrotransposon, and at least one biological function (e.g., capsid formation or reverse transcription) in common with the corresponding domain. A wild-type LTR retrotransposon does not comprise an env gene. In some embodiments, an LTR retrotransposon may comprise a retrovirus (e.g., an endogenous retrovirus) engineered to lack a functional env gene.

[0021] Retroviral: As used herein, the term “retroviral” in the context of a domain (e.g., retroviral structural polypeptide domain or retroviral reverse transcriptase polypeptide domain) refers to a polypeptide domain having sequence similarity to a corresponding domain from a wild-type retrovirus (e.g., endogenous retrovirus) and at least one biological function (e.g., capsid formation or reverse transcription) in common with the corresponding domain. A wild- type retrovirus comprises an env gene. DETAILED DESCRIPTION

[0022] This disclosure relates to compositions, systems, and methods for targeting, editing, modifying or manipulating a DNA sequence (e.g., inserting a heterologous object DNA sequence Page 63 of 356 12806819v1Attorney Docket No.: 2017469-0045 into a target site of a mammalian genome) at one or more locations in a DNA sequence in a cell, tissue or subject, e.g., in vivo or in vitro. Generally, the systems and compositions include a template RNA comprising a pair of long terminal repeats (LTRs) flanking a heterologous object sequence (e.g., encoding a therapeutic effector). In some instances, the LTRs are derived from a retrovirus (e.g., an endogenous retrovirus). In some instances, the LTRs are derived from a retrotransposon (e.g., an LTR retrotransposon). The template RNA is typically introduced into a target cell with a structural polypeptide domain and a reverse transcriptase polypeptide domain, or nucleic acid molecules encoding the structural polypeptide domain and the reverse transcriptase polypeptide domain. In some instances, the structural polypeptide and / or reverse transcriptase polypeptide domain are derived from a retrovirus (e.g., an endogenous retrovirus). In some instances, the structural polypeptide and / or reverse transcriptase polypeptide domain are derived from a retrotransposon (e.g., an LTR retrotransposon). The template RNA and reverse transcriptase polypeptide domain can be enclosed within a proteinaceous exterior (e.g., a capsid) in the cell, e.g., to form a virus-like particle (VLP). Within the VLP, the reverse transcriptase polypeptide domain can generate a template DNA (e.g., a linear and / or double-stranded DNA) from the template RNA. The template DNA can then optionally be integrated into the genome of the cell, e.g., by an integrase from a retrovirus (e.g., an endogenous retrovirus) or a retrotransposon, e.g., an LTR retrotransposon. The heterologous object sequence may include, e.g., a coding sequence, a regulatory sequence, and / or a gene expression unit. LTR retrotransposon systems

[0023] Long terminal repeat (LTR) retrotransposons are a type of mobile genetic elements that are widespread in eukaryotic genomes. Naturally occurring LTR retrotransposons typically have a coding region flanked by direct (i.e., not inverted) long terminal repeats. The LTR typically includes a promoter whereby the coding region may be transcribed. The coding region typically codes for the Gag and Pol polyproteins. Gag is typically processed by protease to produce structural proteins matrix (MA), capsid (CA), and nucleocapsid (NC) proteins that form the virus-like particle (VLP), and inside of which reverse transcription of the LTR retrotransposon transcript takes place. Pol typically has protease, reverse transcriptase that copies the LTR retrotransposon transcript into cDNA, RNase H, and integrase, which integrates the cDNA into the host genome. LTR retrotransposons also typically include a primer binding Page 64 of 356 12806819v1Attorney Docket No.: 2017469-0045 site (PBS) immediately downstream of the 5´LTR and a polypurine tract (PPT) immediately upstream of the 3´LTR.

[0024] In some embodiments, a system described herein results in integration of the heterologous object sequence into the genome of the target cell. In some embodiments, the system results in integration of the heterologous object sequence into a specific site within the genome of the target cell. In some embodiments, the system results in integration of the heterologous object sequence into a random site within the genome of the target cell. In some embodiments, the integration of the heterologous object sequence into the genome of the target cell results in one or more duplications at the integration site, e.g., duplications of 4-6 (e.g., 4, 5, or 6) nucleotides in length. LTR retrotransposon genome delivery systems

[0025] The present disclosure provides compositions, systems, and methods for integrating a heterologous object sequence (e.g., encoding a therapeutic effector) into the genome of a target cell. Generally, a template RNA is introduced into a cell (e.g., as an RNA molecule, or in the form of a DNA molecule (e.g., an episome) that is transcribed into RNA in the cell). The template RNA is then enclosed in a proteinaceous exterior (e.g., capsid) within the cell, thereby forming a virus-like particle (VLP) in the cell. The template RNA is then reverse-transcribed in the VLP to generate a template DNA, e.g., thereby forming a pre-integration complex (PIC) comprising the template DNA enclosed in the proteinaceous exterior. In some embodiments, the VLP is initially formed in the cytoplasm. In some embodiments, the VLP is initially localized to the endoplasmic reticulum. The VLP does not obtain an envelope. In some embodiments, reverse transcription of the template RNA occurs while the VLP is in the cytoplasm. In some embodiments, reverse transcription of the template RNA occurs while the VLP is in the endoplasmic reticulum or another organelle compartment. In some embodiments, reverse transcription of the template RNA occurs while the VLP is in the nucleus.

[0026] Once in the nucleus, the template DNA (or a portion thereof, e.g., the heterologous object sequence) may be integrated into the genome of the cell, e.g., by an integrase (e.g., a retrotransposon integrase or a retroviral integrase, e.g., a lentiviral integrase, e.g., an HIV integrase). In some embodiments, the template DNA is not integrated into the genome of the cell. In certain embodiments, the non-integrated template DNA is circularized, e.g., to form an Page 65 of 356 12806819v1Attorney Docket No.: 2017469-0045 episome comprising the heterologous object sequence. In some embodiments, the integrated heterologous object sequence may be flanked by one or more LTRs (e.g., the 5’ LTR and / or the 3’ LTR). Template RNA Component

[0027] In some embodiments, the template RNA comprises one or more (e.g., 1, 2, 3, 4, 5, or all 6) of the following (e.g., in order from 5’ to 3’): (i) a 5’ long terminal repeat (LTR), (ii) a primer binding site (PBS), (iii) a promoter, (iv) a heterologous object sequence (e.g., comprising an open reading frame), (v) a polypurine tract, and / or (vi) a 3’ LTR. In some embodiments, the PBS has a length of about 15, 16, 17, 18, 19, or 20 nucleotides (e.g., 18 nucleotides). In some embodiments, the PBS is complementary to a sequence comprised in a tRNA (e.g., a sequence located at the 3’ end of the tRNA) normally provided by the host cell in order to start the reverse transcription.

[0028] In some embodiments, the template RNA is single stranded.

[0029] In some embodiments, the polypurine tract (PPT) comprises at least 50%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% A or G nucleotides. In some embodiments, the PPT is responsible for starting the synthesis of the proviral (+) DNA strand. In some embodiments, the PPT has a length of about 7, 8, 9, 10, 11, 12, or 13 nucleotides (e.g., 10 nucleotides).

[0030] In some embodiments, the template RNA does not comprise a sequence encoding a functional viral protein (e.g., gag, pol, or a viral reverse transcriptase and / or integrase as described herein, or functional fragments thereof). In some embodiments, the heterologous object sequence is between the 5’ LTR and the 3’ LTR, and one or more sequences encoding functional viral proteins (e.g., gag, pol, or a viral reverse transcriptase and / or integrase as described herein, or functional fragments thereof) is between the 5’ LTR and 3’ LTR (e.g., between the 5’ LTR and the heterologous object sequence).

[0031] In some embodiments, the 5’ LTR is located at, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, or 100 nucleotides of the 5’ end of the template RNA. In some embodiments, the 3’ LTR is located at, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, or 100 nucleotides of the 3’ end of the template RNA. In some embodiments, one or more of the LTRs has a length of about 100-200, 200-300, 300-400, 400- Page 66 of 356 12806819v1Attorney Docket No.: 2017469-0045 500, 500-600, 600-700, 700-800, 800-900, 900-1000, 1000-1500, or 1500-2000 nucleotides. In some embodiments, one or more of the LTRs comprises a U3 region (e.g., comprising a promoter). In some embodiments, one or more of the LTRs comprises a repeated region (R). In some embodiments, one or more of the LTRs comprises a U5 region. In some embodiments, one or more of the LTRs comprises a sequence that can be specifically bound by an integrase (e.g., a retroviral or retrotransposon integrase, e.g., as described herein). In some embodiments the 5’ LTR comprises a R and U5 region and the 3’ LTR comprises a U3 and R region. In some embodiments the 5’ LTR lacks a U3 region and the 3’ LTR lacks a U5 region. In some embodiments. In some embodiments the LTR is a self-inactivating (SIN) LTR that has a ∆U3 modification intended to remove promoter or enhancer activity. Page 67 of 356 12806819v1gttc cacatc caaag g a a gatataa caag c taaatgtgtgctc ac atgt t ttgttgtttg a t g gctttttttc cgt atggttattaacatttcttedth natga cgtttuaaggacctatgttgttagccggac atcgtattt acatgtttaagcgataaagcatgactataagctttttgtaacccatattagt aga gcgtactta tgg taat tcttatttt a aa ttt ttgacag g Tofat c a caataat tgctcaaaa tgc gtccactagtttgtttgc tt ag . Gegtg bagtagag tagt acga cccgatatt cggcgcagtaaatacgtaattgc cgtg gcetaaatatttatttgag gacga aagattt g tagtgaacalnatabaaagcatctaaatt ttca cttatcatacttcttacacgcgaag gcagcct aggattt tt t acg cagaa agctaca a acgaagt gt tg aacTscagatg atgtgagcg ggtgaa at aagtt acg gatttaat ata t c acca a atgg g ggtat aat ct caaagtccaaattc agcgt ttat aa aan RcttiTgt cttaattagataatga tccttgttgagt ctcgatacagagaagccc at aatagagtgtca ct tagctcacataatttactact tt cg n Lfaaaacattc caaattaagacaatgtaaa tggaat aaaag g atgata atttagtctwohserastnemelen oso psnartorterR TL)sic(suo mo.n otuarofsRTL’3d nan siecchrgaagt acgaaaa aacgactta ga aat tgagt cttat attgcaactat aatgtcttttttt ctRdet of aataa cttgataTdihti saaaaaaaagagtgcaa aaagtttacggccact aggtaattctaatatgta atcta gaagtag agtacga5 L vria q gaaga tt4’o0 5rw p esgaat ctacacagt ttatatagcg actacca ag gaaccg agaggtaattacgaacttcg gtttgaaccgcctgt0- fp 96osd iet_ac ta R T T gg gagagtgagacaga a cta aa gt attaattagt attN gaa ggactg ggtactaaactgac ttt ag gt atttggtc4srnt7i o1a son L _ ’ct aRaagcatcggacttaaggatga cgaca a ct tagtacttactaactaataggtcatacctgactgattgtt tatc att0po2 yrpsna,3TadL' aaw n 5gtaagaaaaccGagatttt aacaa ccccaata aaac aactatgtatgtggagatttGaaatgagatgGc:aatacaagtgtttgtaact.oalnaNprtoltemeoreab R Q E O92 03 13 23 xte,T L SDIN 2 2 2 2kc ro EeF- ’D hytB 5e f se:- 1 u - v F Y -S -i9nr ]2 olGn - L - - 1 be-ott3eaelm L AaiysOysG 8 0m Tb a E_R p AR p_R p CR 6 3 T o _2 T y 22 T y _0 T 08 A0[ aa nniT N B 3 L C 9 L G 2 L G 3 L 21gcaattc t c a ag atactg a aa g aat a cttgta c ttaatccctcctttggcca at c taa aa aattagagttacaacttcg gaacattg g gttg g acataaatgaataactaaacg g cttcgcgt atagag g ttttgctataatatctctataagccaag agcctacacgacctcttccgtgttagacagaactcaagtt aagtataa aagcgtcctcagtgcttaccggtttttgctagaattactgaaaggttaaagac cctcttgttaagtgacacgtcgt a tagctatc ctc agccgtcaac c aa ag gt ttg ctgcttccgcaactacg gatattcttaaaattata tgag g ga aaca ttact tg ggtttg ttatagc agcgtaacac ccctcaaccat atccg gaccgtac cccattaattctgagaaactagtt ttatacttttct cttt tattccgagagtgaatcatgt atttggttatcaga caacc tt ctaacgcatgttt ttaataattt atg gtctttggctgaacgtgt agag ataccgtac attga catat ttgcg5ttg 4ccgagtttgatataa attctcatgtctgattagg actatatg cttttgatattatgttaacaatgtttagccacagtg0tt0-aag a g ag ctaattcata ttttttta ttatttagtatat ata cgaagtca tacatttggc cct tgg taaatactttttaactgtgaatcccgt tg ggatgta tccttttcctacgtgt cgatac aca ccctt ct act9aaggtagttac a at caacgaattagttcaccgta ata aa tgttct at acttcgt tct atttctt gaatttg gt atata ca aagtgtag gtaacatc aggc6c4cgatcttatt atttttattg ca attatttattatactcac cgtttaat acaaa atata attac caaaaatgcaag catca7atacct1tatatactctt0act ctattg ttta cttgtcat aactgt gttt gagccagtcgcaactctcaccaag aagctc g gattaggagg cat agcatg g tta ttattt gttcgata aattga gcatggcgcag atg ccac ctaa agcc agaattt cgacca2tttg atccg gtgtagaac ctatgtta ctt attacctatagtttgttt cgtacaccgcGag gat a tatcaaatgaGaaagaactagaagcgatga a:c a.oN3 4te32 32kco 1D- vye- - 91nryM s Z - n 8o p_R LAR 6tty 47 T E D_T 08 A G 1 L B 6 L 21gtt a g gttg ctagtaataag a t cttcgttt aaa g c c t attaattgagacagatt ttcaat cgttg atctgaacccgactcacccgag g cagccacaccttaggcttcaatg ggaaatagt ca atacagagtttcgatagacattttacctctact at catgaga ctgatt ctacc tattcctacag c gtaggtacccg t gct ttag c g aattgttg gacttggag gtgtgt aaag gtcttacaataatgg gcccg a g gaaca ttg at cat aaatataaata tagttcgctctcg atgtattttctcatcgcgtgtcatgc cgcagatatgtctt cg g gtgtacttacgatctc atcctttttttt atgaagtgat attacgtcccattgcaaaaaatccaag ataaccaagcgggaagcctagtgaagtatcc54cag0 gcgaaaacgttaat ccatttacatt agattccccccgtaaaatttcaaaaaagaatgacgccga aaaaacgttattaatt aaa ta tca ccgatgtttcttttaaagagataa catga a0-catcg aagattaaa aacttgagtt aacgtagtata tcg gt agg gagtactgccttccgct96aagcg4gtttgcgc agatat acgtgtttt tgttaa tcgatagtattaa aga caccaatac cagaaagcgttgaaatctag ga tcttttat aaagt cgcgtg ggatt actatt aa cctcacgc71 gta0ccga a a c cagc g at aga gagagt taccgaa ct cgttttatttgtggtcc ttagt aa gttaaac2 ctgcGccaatagaagaaagg aacagatatt attgGacagagag gggatgatgataccgagccacagccacctcaacgtcttc agcagtgcatcg ttcg g:.oN53 63 7te2 2 32kco 1Dy- - veu -a41 R 91nr- Fn - CoyT s L 8 _ 6o LttE AR L R p T E F T y V 0 B_ 2 L _ 8 A B 3 L G V 21gta ttg cttttca ac tcttc t ttttacgaa ataatccatctc a g ctg gta ctgt cgatt a c g ttcg ata tct tttataagtttcg tataccacaaaccatacgtaggt cggacag ttggcggaaagacagtaaaccccaatcgcttcaatt gtactgag ccacggcccctccgtcagtgtgag g agacatg agtg g acgacag cttagtgtg 672 cta gcgctgcccggag g gcgctttcctgtgttg ccgtaccttcag gttccag aa gcatcgac acaat attgtcttgtgttggccctctt cgacg aatacacg at aaacag ttg gaggccggtaattgaactcgcttg gac atatttattta aggtgctt ttatgtactcact ga aggag act tagtt aagcc cgacgttgagctatttccc ata aa cctccgtctg gtctaagt tttctg aat tg gg aatacagt at aattagt ag gacacgcgtgactcta acat cttactcctcaaa aaagacctg attcat agtt agcagatcattg aatccc aacgaaa ctca gt tcaagttca a5 gccaacgatccg acgcgg a tcattattg gaatat aagtgag gg gttc agattcaacacgctttg ca a ccaac gtgtg g ggac4ct0c0tctg c-cgtctgt ac agt acccat ct tact tcgttacctgtcg tat ct aaacat acctactccgttaaa cccc atcgtcttaattg g aa ccg cccatg ga c tatg at attcag a gattaacatttttactatattgagtttatc agtgaac cg acggc cg9agga cggttatct a cacccgactctcttgatgtatatggatat aaatt gcaatttt cgtcaaacg gacac agatgct tt64cctctc catg ctagagccc gcgtt attggatatatcatgagt ctacc cttttgtcgtctg gaaag a gttgtttgt ta aatat7t1ccgca0 gctatcgt ctactaaattc cgaatcgatgagatgttcattttccgatc tggaggtgtgggtatattctaagat aag g attg aag g gga tgttttgaa a ag tgtgttga tctatgtttcgaatctacg g attctaaaagtttactaaacccagcgccc2Agag atcatctcatgccgcg gGagt atttcccgaatg gcag atgacact attgtgtcG Aaggtt:tactctcaagagaca.gtgtcctoN8e3 9 0t2 32 42kco _4 1Dvye-iA -6 R 9 T 1n-r1 MLIysL 8ottV A F _R HR p_ 6 1 T TT y V 08 A S 1 L A L G V 21a gattt ata t gtctctagtgaatcaagg a gataaatcaaaa t tc ttgttca t attgctatgaccg ctatttgtgaaaaagagaacggttcg tcataccaccttg g tagtatagaag atgg ctttctttgtttag ttg taaacttcatggatg ttg cattcct ctctttg catcattttccccaagttatttcagttattcgacagtattttattg gttatgttctttctttagttgtattatgaattttaaaactacaatcgtcagcac tcatcggtttgctgga caagtgatcg t acgaccggctgttccctttctt ttatttg aag g gga aaag tatta aaaaga agtg gtt agtg atgctttgtta gt aag cttaccat a ct acatt c tt tgagtatctagtag g atgt cctctcatggggagtaagtgtt accttcc aaatgtatct ctaaatacctt aagttctttgttcctttttc tcta attttgattgt aggtattg a g ttcatttcttcaaaatagtgt aa ct tcgtttt ta agactacttcgtaa a5ccg4tc agaag agaatgtatc ctgcactcg atac ctgttatttccgcgcgaa ctttattgct at cctg gta gt ttgtgc tt tg 0ttggaatatttatgtgactt cgagaga0-aaaagt agtattttacaagt atctaaacccc attctat gactccgtataaccaagcaaac cttgt tgttattatttttcgtccta ctgagtatat cacatgagagacaatttag gttttgca gtactt9a aa ct atttttaaaattccccccggtt ttaaaaga agaaaag gca acgg g gta ctt ttcct6at tc ttatttaatcttcat cggataataacctgattttt ctcggagagtcgataaatcatgaaaca ctgtatt gagactt cttgtacgttga a4ccga at aattcaac ag agtg aatagtagagac aactgcttccg gta ctacctgttgtcct cgagttatcttctg ggct71t0aatt atga gt aatgt acactcgtt agttt atat catataccca aaa ttttttta agtcgta tttgaaggctataatatc2 aataatattctgatgag gaagagacacatctg tgattcgg agcccataattcaagcatc cgtaacaGagagt tgtg g gtgtaccccccccttgtagagt actgtcc:c t t c.oN1te42kco RDT 1vye-L- 9nrysR 18o p Gtty _ 6 2 08 A G 3 21g ctac aagaggcaat a t c c g gg tttttac t c c a t g g aa attaaa acaa ctt taatttg ctccgag atttgcttgtcta agactctatttctgccctttcagtacctgtt cagacttgtctccttg aagttctctttagag actacct ataaca g a g gttgt ccatagtggactcccttttttatgagta cgcttatagga cgcggtg tttat cg ca aaacgcacgg gtcaagatgttga cg g gcg ctattacg c gag tctgt acgcc aa agctg ttttataaaggagtt cagctgcttgtcctcg gtctccctcccgcgacagaga ccg tacg g ctg aatcttt c aaa gtccg accgtgccaga aaggagtgtg catg gagtttag ttgac a tca cgttc cattctt gattg g ggtgccg aatcgcgca aatctac taacg gc aggcttcctc cgg ct tca ga cg ag gactagcg g tttcagttct agatttc t5tgaa catt gctatcttacactataaacgcatgcgt cac cg agttcgg ctagagtg cc4cg0tt tcatt ct ag atc at0-aaac tctatttgac atgcctac atcaa gccgcaccg atcct catcatag aaacatca acag gc tctgtctatg g g g ta ctcca cc gacat ccttt cggttcagg atttaatgagc9gcg a6tt aaagtt tattg t4atg cttgaggagcttccggtacc cggagtattatca a ccacaa aggtgaacctgtta c7t g ttac ctcccagttg gctacg actcacc cg ggtcctct gt tacaaatatgcaagagt c1a ag gaggt aga ttcttg tacggcgat cctgtttacgc cgttttttc attgataggag ctatctgttg0tGag g gcc aGctgaact aattgattataccgcaacgccGtttagagtcgtgtgctg c gaag atac a2:a a aga.tt a agttgatt ag g A g ga cgaccg gatctoN2 3 4 5te42 42 42 42kcoDy-e- - 1 -c- v - S A 91nryM -ds ZyaN1 S - A 8 p_Rsp MR V_2 R L_R 6otty 4 G9 T y _ 1 L G3 T R 4 L AT E34 T 08 A E 1 L B 7 L 21a t cagtaactccctattg cta gat c g a ctacaaccgct gta a ataaacttattcgttgta tttggaaagggac a t gtttttaatcaaag atataag tttaatggatg gtactctcctttagtg ttatacg caccatg cccacgtcttacttcataataag acaatccactgtg g gcatatcggcacttaactg ccgattgtcaccgtg g gctgtcgttgagtg g 482 g aatagtcacagaataacaaaagtgcactttaccttacgtaataa ctctgtcatgg ggatcaattt atagagccaattatacttgcctattctgactttc atttctt aacttag g gaacgattatgag ctttatctcc tagacactgcgcaatcaacctttgtc tg gaattgtactt ttctga aagagtgctttggaatac5ctaaa cctg catctaagaaa taatc gctacccttaaagtt cgtatttcaac attgttttgtctaaa tacagtgctctaac tgcctaa cgatctgttgcaa agtttt4tactaattatacaatttaaaaag cgactg gtacaataaagtgtagtt ct ac gctg caaccaag gcttttc atct att aaatcacaat cggt ttggaatg0t0-gttagtgg gctt tttgagtt cgtatgccca tgttc ttttctcaagtatttttt tgttac aatgattt gta9t6aatatgataatagtttacatttatcgtaggtggtaagttatcttgtttg gaggactat ta ctagtttt4 ggtg gt gag gctgcctcga ttccataatgtg gct ttattatattggtat tg c gttgcaa ct cagattg7t1caactgctaaagtgagttgt cc aaattttct aataag ctg aatgataaaaatattattct acactgt ataaaac0ac tG atgt aaaagtGct at ctaatccttGtctatatt tattcagt tttcgtttcaag gttta2agag g ga aatccGataatccAgaacaaaag g ga:aactcttgaaaca.oN6 7 8e4 4 9t2 2 42 42kco T R 1D-yLe- M _ - T v - S -Ln- 91rysZ 2 _ EysO_ysR 86o ptty 9 R p TRIy 9 R p T y G 0 G02 L R 3 _ 8 A R G 2 L G 1 21ttcta t gcct c a gcattgctt t actg c tccttatat atat agaga cc t ctt t tt t atttttttttctt atatcg ttttgttgttatcgtttacattatgtcatctcag acaaaagtctttg g gttgtcctctaattgaacgttttttattatctacatcgtaatacat ctcttcagtcacaaattagtatttcacaattattattccccgatcggtctttatttcctatagtgtattgtgcattgaaagcacttaatcccggatcactattact gc attgtttaa ct agcatttcatc ttc tta gccta gt acgtgttagtatatg ag tatactccag ctgcttcc agcggttc ccgcgtgcctc ccgt tgtg cttagtctcaaacgatccagcttaaaccg gag t aact at caatgtagta aagctgttggaccgg ctt aggttcgt caaaaacg c gatcca atttgacttt tcttt tg g g g g g gctga tt ag gct cg gtcgcg g a gttgaccgtttc gagaaa atcatg gcggtgtctcagtcgcat acgtgttgcg gca a att atcc agag gccagcaaaagttg c gggttct tagaagactgtcga tg gt gag catg 5g4a a0tatatag g tttgcttt tgcatcctcgttgaggtcccag cactcttt tac tcg gtgcgg ca actgga tgttgaccaaaa tctcaatagtttttttct ag a ggcacagatcacaaag gtcg ggagcc ga ttaccacg gt agacaa ag ggcg0- a9tagtagcactggaaaatac agtcgtga6tt agttgcacttgccacg ctgtgttta tttgcgttctat cctttagtagcg ct a4t ctg g gttttt ctc ggatc aacc gtgc cagtagt ctacctgctttg gtat a cgatgt aggagt agatcag7acat agattt1g0aacg ttaacaatgct cagc c tggcgagatctca ct tgagc ccgtgcg gt attggctgaa cataggc agctttt a c c2tttaaa aatac g ta ag gatt acgctctgtcctaatggc agcg g gcttgctgcctcc aacttcagttcctgaggtgt agattcccaacGa cgcag gattatag gca cgccctgttgccgtgg g Ga c Ggc t a:c c a c a att c a c.oN0te5 1 2 5 2 2 52kco T 1DC_ _ vye- - 3 A 9nrysM AR R 1 TM8o p Z 1ITtty _R VL2 T R- T L 6 o A_ 08 A G 8 L E P F M 21t atct gta t ctaggta g c c tggaccgattcagcaagcactagcctataccaca t cg ata gg aagtcagcctgaggtcctg atacttctacgatt ctctaccactcttcactgg g aaacgctcaaagtcg ccacccacgacg g ccataactcccacttcgag agacgctggat cagg acctaatcccccacg aactgtcacctt a aggtag gttgcgcct a ccgcca catgtg g g a gatccacgacttt agagcta atcgaaacagactgcgtcacg t gcagtttag gacc agacccttataccatcg a gctactaattg g aaaacatagactgc atcccccg gttggccgc cg tatattaagag gagactttga agacg attctgctctatg g g gaccaacccctaaaa c cac t a5 gtaacatttttgcagaatagtgct4attaccatgtg atagacat ttg agg ataattgcggt at aat acatttatttgtgaa catccggtcagttgcccctcgaaaatt t tga tctagc00- ga ag g g ga acggagacaaaac9gagcg ggatcgcaaccctg gccg gcgcg gaaacttag6acaactctttacctct4gtgt g ga c cgc ccggc agcgccga a a agg cg ccagacac ag g ggcaacca tga atctttgtctg ggct a ctcccg agc ag gttg ataag aaagcctcac71ca c0 gt acgataagatc ac2 cc cacgtagcc aactcc tcctag agaaagaa at atg cactaaaccc tcGaataagtcGagattg g g gtgcag gag g ccaGaccgcccccccgaaag ggcaagacatg g g g ttg g:.oN3te5 4 2 5 5 2 5 6 2 52kco - 1DR - vyn T -e- A -Lcun- - F 91rysnyo p AsA Dys- n 8tty _R p 6 T y B p M _ y _R L AR 6 7 T E_9 T 08 A G 1 L G 1 G 3 L B 3 L 21ttaattt a ctgg cgctgg c ta cg ttt t cc a tat g ttatta atgatgt a cgata c cttatctgc ta g ggacggtattttacactacttcagtgccg ttgtaattgtgattgaaaggaaggcaagctaaatagcgcactgat aggcccgag acacg gcgacctcaagcacaacccagtctgaatttccaG caaccatagtcggatctatgtaa592 gtg ttaagttaggaaagtag gcctaccataccgcgcctcaggtag gcgtgagcctttcg c gac actga ct ttgt cg gg g t tac cag g atc aac ttt cg gatccta ctcgtcgca tggcaagacaga accataggagt t atgtcttat ccttgc catct at tggaccttagaatatatattgttaagtaagagagtcct ccttatgtact ctctgata cg atccgaatt tag ctgttga ttagagtga tcatatatgtgtagttcta gtgatagccaacta gcct taatgcct tcgga tttgagtaagtg gtctag c ggattggaaaccgcactaactagtt aaagag attc5tcggg4c at tc tacatt cctccctactttcccccttatttg acttatatacacttaataactatcgtgcg ggtgtttttta0gcaatt atata0-aagtga a t cctactcattcttactataatgc gagtaa aattcg g cttgaatag acgt taatttgtttactg gtataga9ca agct aca at tgga ttatactttgc aatatgctccaggctg g aatg cacctcgtttttaagagactagtt6att4ctcacactgcaaattctaggtcgcaaattgccccg atatatgtgaccgc aatgcaaaattcctc gggaattaaagtg tg7at ctatg ctctgtt ag gccccgaatatg atcctgcgggctagaatgc ctgctcctttcttt cg gt gtgtgtcgta atc1t caca ct cct tc taatatgctataactcttagtttag ctgaaggtt a cgtatgtattctttc ctttcgtc agtgagt0c a at2 Gatcg gt a aggttaagttccgGagtaaa tccgct ctggcccGatc aggagaaatcgtgactctc cgagga agcgagctg ggtctcgaactgctattttagatttcttgacc:ttcaaacGatagagcg gctgtacg.oN75 8 9 0te2 52 52 62kco R R T 1DTe- - vy L- -L- iy 91nr- Q o L CysA - B - TysSysL 86ttE_ py _ p_ y 6 R p AR T y _ 0 B46 1 3 4 T 8 A G 1 G 1 L G 6 L 21ataag a tttta ctca a c t cctttttt tacaca ttg ga aac ctgt cggtaga ca ga tgc cccaataattgcgtag g taatg g gaattgttg tcgtttcgtgtcgcat ctttatgagtgttgcatgtgtaaagtg tcatttgtgtg gaaactttt g cttgtg gtg aatgtttacatgtatg atttattttcgctgagatcg ttgtttgtgcg aagattg atc ctgtgctt aatgactg aagagatcttcaatg gatttg tagagtttcacagcgggt agcaaggtcg ga acatcttaatttctctttgttaagtgattgctcg ccccgcgc catcag caatag cacgccagctt gag cc ttacgg tcaatcgttgttcaacac actgccccttc tataagc caccggct ctaatcatatt ttgagtcttt at5 gtttcttttgag gg caact gcggcgtgagggtgagtt aa acccaa ggat atagttcgatgatat4cagagctc g g tttttacttaagtta cctttcacatgcgcggatttca atgacg g gtaggcact aaattt0ca0tgc t-gtc ctgctt gt accagtt gt cggcg g ggtccccgtaagactgttcccttgtt aactaaaatttta catgaga cattt actca agtcctcatcgcg t gtaggtacacaggacaaccaatctgtatgcaact9ctgttattttgttatgttctg ggggcgac cg g c g cccggaaag cgcgcgcgctc cggatagtaatc64cttcgcgtt7a ctgca atgc cg aattgcaagtggacccatcgtacgaattg g gcgacctgcc cagagatgtt1agat ta ttt cgttctca cgtatacatct agcttatcttctgcctttaccccc ctgctca tcccat ac0ga a2 gtgatgacgtt ctccttcgaaaagatactcgtg ggtGataggttccg cccctgcgccgtgccccctttGgtgGaatAct agcgtt cg g gaa cggctcgttcGaaagtttg:.oN1 2 3e6 6 4t2 2 62 62kco R _ 1Dy- T R T 2 ve-irL- LL 91nrysC o p C -a- - Y 1prUF 86tty _R L T E D V R G55 L _ F C_NIT 08 A B 6 S 1 C L 21aat gac t ac gtaacac ag c ataa acta agcct c a g c aaactta t ttaccacaa c tttt ctcctatgaataacg gttgt atcttt ag ccatacatacacctaatcaag ctatctattaaactgtgccagctcttacttaccatcctaatatttagtttaagtgtgatcttgatTaaacg tttagt ccaatatggtcacaccctcatatg g aaggactttactcgttaaagttatctgtag gttgaccg g attggctct gtattaattaccgtcaa accg ggcgtg gccgactctaag gtgcttccgagg aa ccg g g a g cgaggagaacgtggcacgcgatccgcagc tgatttgcaca cagtcctg tc attctt ag g act ttaccggaccg c gtcc cg gctc attggagggagtg ggaatcggagagt ctattcga agct atttag caa aggaagac5a c tcgccgcccg g aca acgggag gatg g g g gtg 4gacgg gcatag aacttattgtatattt tgtcgta agctt ctgttttgagcggc caagcgtgtaccg ggga a acgg ccg gaacca ccgcagtggattgacg atggcatcc acacat0gtat0-ctttgggcgccga cggccc ac g tag cagag gcg g ggccccaaaagca acctgacta ag atgc gct caccca attaatcag ggagatt cgccctgactgag agag gaag g gcagctagagttgaca atta cttcctagattgttct96cctg4t a gagacagcag gag gcagttacgcgccgagaaag g g g g gg gc agtg gctgttttt taataccgtagcacttctgtgag g gggacc ggc acgaggagt cg gctg ggtcgaggcatct agctgg attggaaaaccgtttttca7ca1agagc cga agg gga0gtcagtttaccc cgagg gagggagg gg gg gggt cccggcacgcaccttgt agcggc atttagtgatgtattaatatgcgccaag a g a gg g gac cctgtcaccctgtg gat t atatagt acgcgc atcctga a2 aga g c gg gg g cg ggcgagaagggcgatgcggaGgg Aagcg ggtcgag ga c:cgc a c a c c c a a a.atccgcaagtattcgactttaatctaoN5 6te62 62kcoDCye- 4 1v - A 91nrysvaLI8 p GR HR T 6otty _2 T T L 08 A G 2 L A _ 21ttacg atc ttta tgagcgct t g t acactgtttac atcttag ga catttgtg acatcaa cg g ctg actagataot nae)cenlberefdnecttctttttgcactaca aggct taacaca ct c ct tcc ttg gtacg gg nioteu a Tfiu mgotgacfastattcaggcc tttccactat cct ataccattattg g ca etg acttdtrreqesni d,s e echtggagtgcgat aa agc cggtgc a g gcg t gacgcaagacaao aa ch gc ctarn ub t ctw o nertttt ccc cta ag gata atgt cac a t tggacttttactt atcttga ytgtgaito(oh moacsactaacatactta ctggagacc ctccatcgagt atgttttcttgttatecattcn neRsn hctttTerotRciatgtctgta ct ccttccagg c gc ttg ta gac cct agctged a uiL’au T htatg - Lw caac cgtccgac gac c cggagat tttaa gtaaggctcttcaatqatge% as9 5 estnenfo or,ectacacaa c t ccgcagaca ag gtaag attgttcctgtttacg t ga9 aggrohtm n eiamag g atttatt cgccg g aa ctactgacatGaatgtgcaagca ttgcaag ni , saelerap n ttat shcyacgatgcagtcaaaacaacgcatc gaaa aattt ag cgattcttvaaat a% h 89Gn o naebrestctg ggc c caqacgaatcacac cgca a cggagactatcctattctt)actttaR,elbsoscg T %ao oro virnees_gaattag aaactatt agccga acagc c aa taagaatL 7 Tpfsnpsfeld e melT gttgttggtctttagaagc tgcagaagaatgtg tt ctcgcat a ’9,o .) artnar badeN_ gcttgttttaaacaa atctat c cttcc ttaa cactaatacgtc5(aat%6 w ottceor etiitpen R o Tcat a ctcctt c ctcacataccgagccttaagtctgat attc cage9 tp,oreretehr seu hspsoL'3ttacgt )sylps_atta acctgt agagacgagggtgctctcc ctaactccttaacgtt aatge% mtR(oetatggacctgccag ccgttattaaaarct ltt a59asyttccni , eiT tL ec edpnaalct ttttp gttgaccagtctgcg ggtta g atactaaag tthn )sniSitpelbrttmaactcetatag ac cccatcgacag catgctactaacc%t e e aoa cat attg ctg mnis%nanv tan r q ecgatttacgtctaccaccacagtttctcetevaag 09, sosgsoa m of_agtcgt ag gg ctg gggtacg c Ta ghtatg at ataattth n gtttcttaeiv R a % TpshtiwosriNctttt_gtattatgtggtat ctgtctcggctaacga ctg at54,0st cn h 5 L ) 8, ’naw le .a RctTtagg aaa ctttaaga attgatgccttgtta attttg gtt0-ne eu 5 Rr%f tdb9 q T 0oresBP-pRL'ttttgttagtg atgtgtggtacaggctgagggaattctt6miesL 8os teu e 4LEd T 5_geatacttaaaattta a t agtttta gttacctg gta ata4 da ’ , ri rn Ltctat cgtgtagtg ggtggagt71 o 0 br2o3(%aetb ela’alt gtggtga aaattttca:.me(ta 5 e 7p alyb J3pgt c,yrpam aTsdm cttctcat ta tgtgcttaagcattcttcgg atcccaccoeG pe%almelneTGtatagaga agtatctgag gcgtcgaatctcpesr.baNtmelr0teobala7me e ew viola R eTT Q O0kcsnITfni tsaxht rEfd b,niL E ’ SDIN14 oD omyer ]3 reeloenttaeditP- d51v ]m pLes :et- su J al- Y 9 L 1n3 g g 4anesoepysA 86tt3 m 0un lolni3ep ylelbe lbmepy _R BT 08 A0[oc ’v3a0 h0[h T o p amTaa n T T G 5 L 21tcttt attt ggtttg gtttttgt cc tttccatttgta ctttcg ttttc a tgag gct t g t acactgtttac atcttatgcttt attt ggtttgtttttgt cc tttccatttgtattgt a ta c ca g tctggt tttagcattttcacgcttgaatg agtag gtgttttt aaagtttgtagattg gttgtg tcgtttg gtgattgattg gtcgtagtatctttttctacaagtg atattttcttg gataagagtgat atatag tcgg gtttacg tagaggtaaa gtgatg tttgcgtcaggacctcacata g cgatcttcagcgccttcttgtc gcgcatag ggt ag gac tagtgtatgcgattt tttcttagtt catg ctgttcgcg ggt agcaagtgtaatt tcagt tatacttgca gagtgctt atacg attagtacta tacacacgat tttag c gctctcc gtcacc atacagctt atactcg aagttatcgaacta tcacgttttac ct tagatcgt agagg ctg ggtacg gttac ct tag cattg gagtgtaatcata gac acgtttttgaat atggt aattg cgttcattcttttc acctag gagtgtaatcata cta5ttgtcacatgtaa tatgt ttc at tggttcgtcttatgca cagt aggatgaatattctttgtcacatgtaactat4a0aatggtgtgttcttatcc tc a tttagaaatt a aggtgcctttt agttattg gta atatggtgtgttctattccat0-tcatat ag gcgtg96gtca cctttttgttagttg atgtgtggtacagctagggaattct atc ta ttcag gcgtgtca cct4ttcctcgttg tttccaa g tga a ct aaattagagtgagttt acctg gttata ttagtgttcgcgcttttccaaa7ttgc1g0ct acag agt ttaaaatt atctattc agttgtagtg ag gta ggtt attgt tctt tgctacag agtgttaaatttc2tt aacatattt cg g ggtatgttcgtttcggatg t gtcaaacaacttcgt aacgctctaacatattt cg gtg at:t.aggcct gt ttattt ct cact G ttttag ttgtg ga at tcta tggcatccgcactttta gg gttcct gtta ttacoa a ccttt c a a a agag g gc a c c a a ccttt ctaNte1kc14 o - 1Dvy9e- YnrysL 1 p A 8 R 6otty _T 0 GB 8 A 5 L 21cacaatt a gtggaa t a cta ag tca agtt ccatttc c gg ctactcgttgcggctg t a g t a cgtc c cggagtc gcctg gtttg gccga a c acattgcgatgac tcgtatga cgagcttcgtgctcgttgcg tagcgtcctg c g cagcctacctatccccggccaaagtctcacgagcctg ggcaag gt cccg g g g ctcccaacgaaaag tag cgt cataatag atccgaaatactg g gagcgctcaagctgt144 taa gtgtccgaaag tcg gatccgtttg ctttatccaccactgcccccc g c g caccaaccggccacc cccg aaa ggttactc g taggcgtcgcgag g g g ggtctttc cttgg gtacagatccgggt cccacgccg cttt tccaacccgtcaagcac agtg g gggcagg acgcgtgacctctg gta ag g ca5taggagttcccg g gctgcc agtttaa ctacacg ttcgg atg gccca cccc ggcg gttgcgcctg gc4tt cccgagccgat c cg tttacgcgatagcgactggaggc tgt gtccggcactccctacccag gg0c0agggcctccgggc cc t-c g gc tct cttttaatcaggcttgtat cgtg gtcacatccccgtcccg ggtt9actccgccc aga ccgtt cgtt cttggcttatgctcctaccggc tgtgaccgc atcgtat a cg ggtct6ag a gctcgcgccctcggac ccatttccg 47aagtc aaagtgcgtg tgtccgat ttggtg c gccg g ggg g gtgccgaagc1c gaagacccgatgcc ggttggctttgag accagttcgcgtagag agtatgggccacgcgttgtt0aga cg c g g ggag c2actac caaccctctct caaccagttag ccagcgaggtgcttccgttgcccgcgta gga:.Gtcgcgg cg ca ct gc act ctg gaatta ac cccgtg gc a cct c cggtacgaggt cttaagtc cgcagaoa c agcgattg gcttctacgccGagcaaagcctcgcgtaaGaacNte2 3 4 5kc14 14 14 14 o - 1Dy- R v9e- -cna-vrys1a- - AT y D N L 18 p MR GRs1 p B V_ 6otty _ V G6 T 1 L F _T y _R o T RP 0 S 02 6 8 A L G 2 L E C 21tct ccgactaaaaca ctc c cctttttcca c gttatcactcaggattgatgtaaa g Ggtaacgac c gcg acacccctcc t tcac cctcgacattcatggtgtaact catcgtatg ctgcg gcgtccctttctctggg gttcctgagttgagaa ccactcccttttttttcaaataaag gtacacgaatctt c a g ggg gtgtgc tcag g c gttg gac cgcaaaccgcaaacttcaaagtg tcagttagta gcg g gctctata tcttatt cgc tttt acgtccctcacccc atcagttgatcttggcaca attggattatg gtttc aaattgg a gtcatggcttcgccttcctccatgt agagtcttgattgaaatt gtaactaatttgaaatccat5 gccg4a0c c cgctcct tgatcgcg gcgagtggaaaatgataaatatca aggagtt ag atgcg gct agtaagcttg g gatt ctctgcgctcacggatctgtt tca tca ta cg c g atcttt agaattgt acttt0-ga ag gc9tcct ag6catctatgc tcttctttt aatcatcag ggact tt cat at gtgttg gcgt cgccatgtccctgag g aacccgctcctttgag ctaaa tagtcaacttcataaattttcttcgc tata4caccat a ct ctctcagcacttttac ga tgtattatattaattaa ttg gtttatttg gcc atagc7 g g 1gggct ctaagca cgtcaag gccaagaagtcttccg g gcggaa gtcagagctt atttat gtg c0ac ac2 ca tg cttctg cctgccagtttttaacagg accttccctaacgaac aaga gtcgaact atggact:.g cc cgttacgttcgtctcgtGccg Gg gta agccat agtttattaaagacc att ccattgaaoagctcctgccagtccc aAaaAaagtaatctactggag gtcccttgctgNte6 7 8kc14 14 14o 1Dye- - -rv9 -v- S - 1nr1aGyRsOyA 8 p_sG 6ottVF _T y 9 R p T y _R T 0 S 61 L 3 7 8 A G 2 L G 2 L 21tttccgcg tctgg gtcgtc gaacat at cat t ccagcctttgaa gtatc t atacatgtgaattattgacttttcatttttttgttttgattctgaaact aa gtactc tat at g a gtcgcgacttttctagcgcgtg gcgaacttaaagcg ttcagttttg atttcacatatttcattattt ataacacgatttatcttagcgtctccctatagttattg gcg atatgctgggt atttcg ccatttaagtgatttgttcg tcatg gctccaa cctgg at taata c ag gaattatcta atgtt acattatc g ctggt accgctttaaggtatgcct agacatgctatcaaagatagatta gaac attgttccgagtgtgttaca acatgaaagccgtagacacag ccgagttctcttgttatatt agctctttttt cgatttattgtttcttggc tgacatttagag gtaatttac ctcttgtcttgttgacg aatt tata atact gctac ttatatcttaacc attgat aagtaacgtaactctgacatactaga54ct ctta0cc cca cctgtagtgcgga att cctctg a gatgtatt aact ctaatt atgttg aaatca taatctttaacatgtg g0-gg attctctg9t aag gtc cggagtcctacaacctta gttgtctacta cgagtactaaacc att gtat tgatt tttcacggtaagtggtattag cttattgt agaa aca ta tta tataactt catatt aattgtaagtagacttcagataga ag6a4aac7tagccgcgccgt ttgtc ttatact1attaacta ag gcc gt gtatgtac actatt ctt gtagttaggaccggaatttttatttggagtatatg ctttta tctgagtt ccatttttcattg gttta ctt cgataacagactgaaattttaa agt ta0catc2 gagtagg g a gtctg aa tatgttgtg gtaatgacgtaaatatttgtttattttttttcaaataact ccaa aga ttaa:.gagttggtcgagct caa ct atataata cgga agatcag gcattaa acgtaaatttactttattaa ag atattc ctaacgtoa c c a c acttatcataag atg gacgtGa cg gatttgaggaatactcgtcgtattttacagacaga agNte9 0c1 2 1k4 4 24o 1Dy- G ve- S - C - 9nrysOys_ - RysR 186o p_tty 0 R pBT p GR T y 2 L y _ 0 G4 0 -i7 T 8 A 1 L G 1 G 3 L 21ttt g gttca tctg gttca tctg gata a ct c g c a a cta t a t agct a actg gccgag gccg atg tt c a tgc aacaaaga ctc taatc atgcc tc atagattttcatgttactttaatccatact ag atcttaccacg gcaaatagtctt agctatt accg cag ttgactttt ag gttctatcattttatcatcctcctattttcgtcttaatt cgtctttaaaag ttcaaaaaccgcgactatacatatgttctccttc g a g ctaaatcttcg aag ggttcgagtttag g tttttcgattttatccttaatccg tgtgcgaagcctttcacctat c agaaga tt agtatag cagg cagg gtgatgcccg gaa accg gctgtatgata agagtccattctatg gcggagt aagcccg ca cagtatc agctg atcga cc gaaaa acga ag g taagtgagtg gct tgcgt cg ggactg atctt ctg gagtttcaattttg actg aatccg g g catccg gtccc agcagagtataagtcg g gcaac tctgaac ag gtt aaat atttc5cgac atagctcgctc g a aattccttagctgtg gatg gtg4gt ac ttgta ctgtgta gtgta gt a ag aag t ttat agaacg0t0ct- ga9attcaagttgctcataa aaga ctacaaa ga ctctcggttagc tagaa cgtc tgcc g aa cgtgatcgagcttatttgttt6ac cttgttttgt at ctttca ag ggctca ag ggctg g aacc aattgaccttcgt ct tcgagtggatcgtacgagggacct ctgagttca cga tgtgaccattgtgaccaattacctaggactgtgtaggccgtttttttagaga ctat aggtg47 g 1aagccttt attttcta g gacctg g gactg t gc g gtaactgaaatagtataaag atc tgtccttatctgtt ctgatgttg0c2tg gt gacat:. tgttcct gc tcact cg gataccct cgataccctctatg gaaa aagtt gt cttttgacg actttt aggtatctgca tcttt tgtaaga acacttagacacttactgttg aagccc attaccgtctgtatgaa tg gaaatggctgacttaocgttaattggcGacctcatGacctcatgaacg gtag g g ggtacaaGagacactgtc tgNte22 3 4 5kc4 24 24 24o 1DT T vyeA L A -i9 _ L_ mR - B 1nrMIMMI- M 1 A_TysS_ 86o TttA T T F _ 1 R A T V1 L p R R -ay 1 T 0 F _ N 3 8 A 1 R E 6 R G 1 L 21tcatttgatgag g g g attataaaaa t catttgtca c t c g a ggtggtg ggag c cttcgtcca gggt catt a c gtacctg ct agta ttcccctgaaat gt aatga tt aa tttg g atccctttccattactgagtttg a g actg atgtgcacg gagcgtcgct g aaaacg ctgaacg ggactttacg ggatggtattg tgcattg aagtggaatagaataatcgatcgactgct acgtctaaagac t tccttgatcg acgtc g cttgtaccctgttactcaacag ttctg g a g gggccatgc gctatattgaagtagcccag g g gcctcacaagagctgtact cacgtttcttct cccatggttttgtatggccagttag t gtctcc aaataccaagcg g gt atctggcc ccaacttgacttctag ttgtgaacacaataatgatagtctgatctattgtt tcgacttt atc a ccaaccat cct cttaagtaagattccgcaat gcttgtgtatg ggcattacgatgac ttca at taa caccatccg gaatga tg gc caccg gc cgtta gc aatcg ttaatcctt5tac agcactaaacattgc atc ctaatggt aa gc4aacg ggcg cctcta acctta gcc ca cgtataaaat0 gtgctacatag gt cgttct atg gagag gg g ggcgccttgc ctctagtcctttctagtgtatatcatt0-gagc9ggcgttgataatgat c tggag g gggatccccctgctttg ccttgtgaatatgt gt ag ggt atg gtt6cgca a47atggtgcggat caa agcatgcagt ct ccgcgttatttggccgccccgatc at cctggacagt aaag1 g gg0atac catca2gga a ag aaaccgggcgcacg gtttcccagcg actcaccgga agatc aatacat atcttgtactttagaccatt:.gtttggat gccacaa tacaatatttgca tgcc cgcga gtctggccgcg gcg g gaaaat to g gagcgagt agGa cgcggctagatcgcca agtcctgGaaaatgctatctttNte6kc2 7 8 4 24 24o 1D-irvye- p - C M Z 91nrysB o p DysC - _Rys_ R 86tty _R p 3 T y B2 T pB y 7 T 08 A G 1 L G 6L- G61L- 21a gtgat ctgtcca gggt catt a c gaca c tttat aaa atgggtcg t gcagacattcggatc c t tca gttag t gg atatgaaa ta t tgcggaagt cgtgatct cg gaga cattacaaacg g gaagtagttcccaccaggtg g cgttaggtaatgttgaattagt aaaaccgaat atacctag aaacccgtttccaatcgtaaag tacagcgaacaaaagtgttttg acgtgaacg acatt ctagatt854 a t tagtcaaccttttgtgag g aaaaattgtaaatgatctaacaagttattag gtattcg acaataag ttttat agga cccaacaccag aaatcccg ctcagcgcgcaagttg gt ag gctgtgtgtgtgtg taacgcttta actc ggagtg gaagagaagccct ctgcgacccggtgt ctc t attaagtg catgtgctattaaa ttggttaacga aatga gagagtcc ccgtgt gccgagcgagcgct cgtt atta ag5gtctgtcg gcttatagaaatttg acg gaacg gga gata atcttct agtga cgg g ttgcggcat tttttgctg4atga0tta0c a ctctagt-atgta a catt agacc acgataaaagt cgactagtaccccgtgcgtg ctttcaatcg9a gtgagatatt gt agacatga atg g g g g gg gc att tggt atg gttaatcacatgtcgtcactgaga at6a4acgc aatttatagtttgcagcgaga gatc aagt aggtgtt gtta aatgccgc gag cacc tcg g att aca71cagactgtctagac aaaataatctt ataaagcaagtggtttgtgtgcctatc aatgccc actgc agaagat0atg2 ct t ctttcat cgtggaagtctgtga agttgaacga tgtagaaatgggcgaaactatt cctt c tataatt:.goaactcg gtgaaaGaaaatagctgctatctttgcaacgagtgcatccacg aaatt cgggtcaatcg Ggg ActtcgacgacaGagtacacg ttatctNte9 0 1 2 3kc24 34 34 34 34o 1D- vy-en M A - Z - _ - -ir- M 91nr-o L DysttE_R pB 2 T y 7 R -prysCysZ 8 6 T V R CR p _T y CR p_ _T y 7 R 6 6 T 08 A B 2 L G 1L- E 5 L G 9 L G 1 L 21ataa t cgt atccgtt tgtatg a c a c a attacaaactacctttttaatgtg att atcatttgttaa t t ttacatttg aga at ataaagcac tc aaag g g taaaggc taaaatctcatttttttccctgttccttcc ttggtctatatacattatcatttaatactcgttttctt g cttatgtggacattaggtctcaggtaagtcatttg cgtcttaactcag gttttcatattcgtataagtgtacttgcaataactatttaaccaaattacacccgctgggaaaacgacaaggaggatattgacctg tcatgt aaaa cttt g gtaact tttt at a ttatc t acggat ttactttagtatttttgatttgaata att acgaaaaggcgtaaaa gattatac ag a aca ataatttg gtgagaaa ccatttttccgttacactgtg gt tttaaacgt ttgtccgccact aatttta atgtt tttagttaaatttctatt ttaactacagcgagtcga aatttaaatct tt tataattttctgta aatg gat cct cgg ctctaaggtg catt ccctttc atgttcactcactactagcatac agttg acta5 gtg4 g gat ttgaagattctt taatacatgtg g gcataacaa ttaa cttggaatatttgttgttactgtg gtcacgagctttactactg0g0att-atcacctgcaac tttgatgg tcttgttacacta atttcttgt aa cgtgtctttt atagaatatacagtgac acccttaata cgctg gact9c tttactttaat tgg gtctgttaaccgt aattt gaa ag ggttcttgaac ctc agagatg ggaactcgccgcattag c6ct4ttaagtttgt ttgaatc g 7tt ttac taataa gtt tttaacagaa attgatag ac accatga ttttt attaggatggtaaag atcacggttt acca tgatt aat ta ttcac agag gata tc a aca ta tcgattgcttttttgatttcg atact agaccaac ccacgtttca1ttttacagataaacttgaagtac ttcattgaag gctttttagtc attgtctt ataaatcat ct ataatctcg caa cattacacg0a2c ta:cgaaactcttatg acaggtaaaatacg ctta actaagact agat cttt ataatttaatgctctttgct ag gc tagtctatca.taao gagactca atatacatctg gtg aaatttgttttagaagtcaattttg ctgtcacctttacg agata cgaattg gttaatcccgagaagatctgt tttttccttcNte4kc3 5 4 34o 1D -yi- v9e- G 1nry- M s CyZ 8 p_Rsp_R 6otty 83 T y 00 T 08 A G 1 L G 2 L 21t acc a taga g tacgttgaag t a gagctaa t catccgtacttta g g tgactactagaaaaaattgaaac att gtca t tgc c cggatta a g cttaaactattatatg ctg ctgtaaggctacctatacttattttacacattattg tcataagtt cgtctg accttttcgttcaaag tacacactttaccgttagtat atag g g tcaagagtgatagtacaagcag tatcaagtat acgatactcaaattt gcg tcct ag tagcatt ap ttt tca attacagggata cgcgaaaatattat ccata aatm 7 tctc ccttagtgta ac acactta aggccccaata a tgta ac o,tgataattttc atg cctagtct ccct t at gaaataaataagc tgactagt cccag aac ca aac% t 0 tgagttcggcttt atat tgat cA 7 g gcggtctt gctgaatatcgaccttgtggttaac atttaagt ccccct cataagttgcg g gt at cttttccNtgcagt attttt c cactR sagtttgtat aacgtattta ggagctatgtttatctt atcaagggacctacg getelgctgcg aatggggtacgttt tt at aaacal tcttt cacgtagtttaa tcataatt aagtagtagctttataggtcaca atgt tt tt ac gaapaaaa gttgagct ctc tta ttccagam g cgt cagt cattc t attaaagtgtattata a ag g gataataagttgg gggctattctggtg gca tttcttcgtttgtgtg attetnivtat a cgct cg tatta aaatcg gaatcccggtttatatat agac egcagcagtttgcgttg atgactg gtg gcgcaattg gctgaht,h54cac cgtgttgtgtg gt0aactt aag gaa tctctttcaa cggacac tcgtctttg atcta taccgaaa cgt tttaaa agtctstecn0-tt9acctgcaattataat cgag g g aa ca catgatt6 gg gagtaa g gg gtaccttg ggactga cactcc atane eu g ggttaatt taatq4 ga7 gaccatca1aaaacattcatagt aaa caa actcttttata ttgcgaaac attag cccgttattttcaa a tctttgg ctcmiatag t gcttgcc tcatcaattgtcaat a atagttgttdesg g o ba02gga tttttg:aaattaca aagg gat cacagcg gatagtgtatcro.cag o gttGagtcacg ttatctta cgag agag g atcagtaacatcg ttgcGg aaagtattaatccgtmee(JNtmele6kc3 7 8 o 4 34 34s baonITfD-yFe- _o1 Z3v9nryM n s Z - A 2 R _R NT]n 1 5 86o p_tty 7 R L T O L m T EBLE_ 3 G61 L 9 - 0ul08 A B 3 u Z M0[oc21fo S.oelecBtnPee ar beaO T QNht fE 3 4 5 6 7 8 SDI4 4 4 4 4 4 94 05 15 25 35 45 uq,3 3 3 3 3 3 3 3 3 3 3 3 esst eoane evit5n romimale m ( d o orulR bsnsTInocS Lme .oiftoB P ’5eel_ b utiS Belb e mahtot tsshcb P uaitap sn a ssim aI. e3 S o Jf relH oo B C_ baeln,P na m 2e a a c at tm g g g g ggagtataaa agaaaaTba ,h u g g fT ul1 tggag ggtacgtgggtg g g g g gtg gg o.w oremasehtfo5n m uloc,otg n,idroc,caecn,eu qes,a % h R o g 09tTc sebiR h Lcad tap T h ni ,ti ’em Lcta va%5w 3dcmneetso)CsiM 5esnc(_ 4 h)8,uau qys_sA 00- R 9 T %rRe anau N C T 0 o 6 L 8fTLsaerem oRutG A T C T A T G T C G A C C C T C T T C T T m _ A C _ _ C _ A_ C A G G G __G C _ _ _ G_ _ _ 47’ ,S’sh o Salte sal s ssip psr psps13(% B P5aH ahw _ n B y y y P A M L A L C HrT AeS A A 02t:.a5,d e 7,yrhotSster tu opNet r%al iB pwPel07 deneeea r R R R R R R htminig o T T T T T L- R R R R T T Rkacni tmsexerioa ,d sto nf LE S -L-L- L u Y S -iT T T L- R T G ML-L- L- L_iT LDmarelE p b snemye e“B F d P.n L O_ C Z_ n uFaV M L _ A A_ 2 _ 4 A n CoV- A 1 _ _4 V vettnrga ig]H mi e elt_ 2 2 iHe39-20 -37 -1- D_ A_ F_ 41 1 1- AV- 9 LI6 18o nnti6 d mttol3elo ’v0bab os neel3-,b m Laiypsypsyps6-2-3-yp L L Ls1ypsV H p 60 a a E o y y y E E E y F T y 8 A 3ah0[TmenIH T N B C G G G B B B G S A G 2155 6 3 53 ccg g g g a g gt gtcg tcccacacccccgtggcg g tgt71 8 3 13 C G G T G G G G T C T C T T T C A C G A A C C C T C A G T C G G G G T T5400A - A T T G A T T T T A T T G T T A T C C T C T C C T T C T A A T T T T C T A T C T 9 C C T A G C C C C G G G _ C T A A A G G T G _ T G A G_ G T C G T _ C C C C C G6 _ 4__ __ _____ __ T__ _ ___ _ 7ue sygrgr rysygr syteue rhrhor_enr_r_rp psp1 L M L T T Pls s sIh y hulpA T T T A A GrrTeygr sL L A A T L A S L A A 02:.R o R R TNR T L R R R R R R T R T R R R R RteTLT - -L- cR T TL- T L R T T TL- n R L- T R T T T R T LL L- R R T RkcL- S - T R MdaS_L- M SL-L-L- L o _ T AnLc-L- A u T L o -L- -i -B yiLrT T RL- T C LL- TvaL G Z_ 2 A Z R O R M P M D F A S -apL _D_y2 4 M 9 _ A A _ _ Z 3 _ 90 T 93 G_ _ C T A M n 2 _ _ _6 B_ _ Q T _ A C 7 A C _1 63 _4 _5 YrC _ G 2 _ C 1 2 4 ve3-1-4-1- 3 N 42L2 1 83 A1 1_ _ D _ L A 9nrysysys17- _ -ys2- - -A Eysysys1M- -3- 9 Iysysys341 1 6 5-6- - - -_2-ysysysys6-1- 1 U - FysLI186o ptty py py V L p R E yRIpy py py V T p R y py py L L py py py p L VNIp H 0 G G G E B G R A E E y E F y T 8 A G G G E F G G G B B G G G G B S C G A 21fo.oelu St bH Be a_ PreT d S a,ht ferB st eo eeP_aaaaa at gagta cgaacata aa taanv6eeita nnielg g g l m g b nigag ggag g g g g gaat g g a gg gggtggaggtccgcgag g g ggcgtgagagag g gg g g gacgtg gg g t g mim d oerulEpctcg gg gaggc acggt c c cgco bssn noc_etm gtggtaoc c cc a acaca tgcc ccgtacgacag gctgccacgagtgctgcmIofalCc cecagcgt cc tc gactctccc c.itop _cccc tct agc ccc c tccccccgcceelutiSmenatctgcggcggtggcggaggcggctgcggtggcggtgttgttg tgagcg mbatsBP T mgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtotb snI.KelbaTnin wohseraJelbaTfosriap R T L’3dnaRTL’5 ehtR och Tcsebitn T _ A A A L A T S L A L S M G G T A tiL’a dapart(w3 ecmem dnetsosu 5esn u C o 40 ua0- rq ys_ m 9 o Resaenao m n 6fTLa reuo4 S 7stu 1 B’ ah H 0P 5 hw _da-2:.yrah S,Bsterno R RT n R R oaltiPneee rT T RT R R R R RT RT R T R R L R T L- R T T -aTNpwetemkedhtminig oLf-L- Y YL- T L T T -L- L T _L-L- LLiT L_ L_ R L-cxer ,do n S L LcavaD o S -r -S G CL- miPvaO A O _ R MM A B So Eiastb EDpnem “B A Pe_ A_ M T T G B G _ G _ B G _ _ _ _ B B _6 _ _6C- _ 93 _7 0 2 _ 1 1 1 1 1vys ede : te ]i mi eltK al5-5-1- 0 2-2- A 6 N2 24 1 0 1 7 3 A A N 3 1 9 11- - - - - -MM 6- -1nr7Joetldo mitpyt3 o 0bbs neel spyspysp 1y, bmey y y Vsp V 1yF y R VspyspyspyspyspITI1 T Vys8 p 6 F y y y y y A A R y 08 A0[ aa TmenIK T T G G G S G E S G G G G G F F E G 21cgtgag g gtgtgcccaaaccg c g c g g g cggagtg gt31 4 5 15 A A G C A TA C G G G A G C G G A Gnat / S A T G A G G G G G G GrtS B T C C C C A C A C C G C C C G C C T C C A CorB P G A T T G T T A T Tt PfC A C G C G C T C G Ter oT T A C A C G T A C A Can A G C T C A C C C C R doiC G A C C A T A A A C G C C C C C C A T TLnataC G C G C T A C A T C C T C A C C C Ce ,slcifiG C G G C C T C G G A C C C G C T G G G G Ghtled C A C T C C C A Gfco 6 G G G G G C C T Co n m53 G G G G G G G G G G G G G G G T G G G G G G SaB dfA T T T T T T T G T T T T P m e unao3 vih,nin 9 e 48 5 6 7 8 9 0 1 2 3 4 5 6ta toint4 84 84 84 84 84 94 94 94 94 94 94 94 n eecgaehs lP tferepso,esn c A oitT AnNacT C TT AT TT A T C TT T TT T T Teu Rt ifC _ G C s_ysy_sG y_C G ry_sA T C T G T _ yr_ C G C C T T q hiegr_s_ yre_sy_s_r_sesttineL y d L C L T L S A L S L h T y Lehwtyinitig lnai itnbitanre 5 oc40cp n0h m o-9caocc6ersl4 oia7K f tde10 d2R R nerdl:.R T T RT R Ra ee an o TL-L- RL- R RT T RT RT T HnioiN L-irMT MR TL- L-iL-L-L- RTsgtitep C ZL- Z TL-iu r MG MMF Lelb neddkcB C _ n _ o D _ _ B BL- C Z_ C_ Z_ Z n _ _as AD3 Bye1- 2 7 A 6 6 D 7prC 7 8 0 7 A_ M T Za .S 1 1 _ 6 v 21C _ 6 3 0 6 _9 1 1 2 1B9 _wtB 9nry-spy-spys2- -Lys5- -Vy- - - -sysysysys3- 2 N L] a8 h P 1 te86otty y py E py G G G B G R py py py py py E O E E 30 SvBit0 a 8 A G G G G G B Z0[P n 21Attorney Docket No.: 2017469-0045

[0039] The template RNA of the system typically comprises an object sequence for insertion into a target DNA. The object sequence may be coding or non-coding. In some embodiments, the heterologous object sequence (e.g., of a system as described herein) is about 1-50, 50-100, 100-200, 200-300, 300-400, 400-500, 500-600, 600-700, 700-800, 800-900, 900-1000, 1000- 2000, 2000-3000, 3000-4000, 4000-5000, 5000-6000, 6000-7000, 7000-8000, 8000-9000, 9000- 10000, or more, nucleotides in length.

[0040] In some embodiments, the object sequence may contain a non-coding sequence. For example, the template RNA may comprise a promoter or enhancer sequence. In some embodiments, the template RNA comprises a tissue specific promoter or enhancer, each of which may be unidirectional or bidirectional. It is understood that, when a template RNA is described as comprising an open reading frame or the reverse complement thereof, in some embodiments the template RNA must be converted into double stranded DNA (e.g., through reverse transcription) before the open reading frame can be transcribed and translated.

[0041] In some embodiments the template RNA has a poly-A tail at the 3’ end. In some embodiments the template RNA does not have a poly-A tail at the 3’ end.

[0042] In some embodiments a system or method described herein comprises a single template RNA. In some embodiments a system or method described herein comprises a plurality of template RNAs. In some embodiments, when the system comprises a plurality of nucleic acids, one or more nucleic acid comprises a conjugating domain. In some embodiments, a conjugating domain enables association of nucleic acid molecules, e.g., by hybridization of complementary sequences.

[0043] It is understood that in referring to nucleotide distances between elements in nucleotides, unless specified otherwise, distance refers to the number of nucleotides (of a single strand) or base pairs (in a double strand) that are between the elements but not part of the elements. As an example, if a first element occupies nucleotides 1-100, and a second element occupies nucleotides 102-200 of the same nucleic acid, the distance between the first element and the second element is 1 nucleotide. Polypeptide Components

[0044] In some embodiments the polypeptide driver includes (e.g., as an individual polypeptide or a domain of a fusion protein) a structural polypeptide domain, e.g., an LTR Page 94 of 356 12806819v1Attorney Docket No.: 2017469-0045 retrotransposase structural polypeptide domain. In some embodiments the polypeptide driver includes (e.g., as an individual polypeptide or a domain of a fusion protein) a reverse transcriptase polypeptide domain, e.g., an LTR retrotransposon reverse transcriptase polypeptide domain. In some embodiments, the reverse transcriptase domain is capable of reverse transcribing the template RNA, thereby producing a template DNA.

[0045] In some embodiments, the polypeptide driver comprises one polypeptide. In some embodiments, the polypeptide driver comprises a plurality of polypeptides. In some embodiments, the polypeptide driver is part of a polyprotein or a fusion protein. In some embodiments, the polypeptide driver is not part of a polyprotein or a fusion protein. 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Q A G V D GYIT G K P K H V V Q P G G S E2 mL’7qereA W L H T L L S K A P LFIS S:. e5,sv S P E T T S L Q A E L E K P D A M Aoe e%irN T L P H G V Q S P Q N T L W HLIDNm h 01rD C Q Q A P FEIQ P A V M K F Y V R Cteokcs t7 oet tsavirQ onI sE O 9DdelDD1yntSIN 3 venr ]o 6 pa:sB9 n 18tegel e- A 6ot40rrnivab m a a L E _ - R 0 N 3 u T 8 A0[och T B 3 F L 21L OP TCSIE T T R P A A Y G V Y D M A PQIW R N S S F ELIP C G E W A L Q F A S L P E G E N Q F T W L R P S G T G P L T LVID D P R T R K M T G W R K R T V G N D DAIF A R V V N S V K Y T G G V I A W R R L L W R Q K E V W N R T SF T E R L N L F EDIK N E Y T K F T K F Q C Q S E H L M E S R G E T E Q V K K E R Q N G L T V H A A E K Q A P G R G E E K M S V R V E L S P N K L Q ESIL F F H N P N R D G G S L S R Q R R F E G T L R V E L H Q H A K K K A S K T R E V Y S E V E T K R 5 F 4 AAIS K L V A L AYL G E L V K R E K S T R V Q Y H K V D D L TF E S L 0 VIA Y0- F H W R P H PIM R RIG E S V K E C LEID E V D L S W K G K E E D Q E N F E W 9 Q L Q Y E E W S F L W A S Q L S T YHIK LGIE G H T T G N P L Q N E QLIL KIT C G K R L K NAIQLV C 6 NHC T S A M Q G Y G L SIS M A K K L47 Y V R RIN P S A G K R E D D S T L P 1 R V T K F N K DEIT Y S A GIIT D D D A 0 R P P R G V M L R E R K Q YDL R F V S K A Y E GIG D P R C G V M G D W L S T2S H L R E A A E R K L L KQIR M P F G Q G S T H R K V L K A P A C V F L F:.D E K L P G Q V A K R E G D S G K N R K Ko S E L V C A G R L L S R V G S G F F ERN V R A C V T A N G LSIV F DIKNE V G F L S L N W H C M Q V K E S Y L Ytekco 04 1Dvy9en- 1raiL R T 8tp A 6oto _2L- 08 A C 9 Y 21L O P F R DF D L A K T FID A L QIE T G V H DIQ V K K E E V L E RIF H H R V DIH K T RS H Q VP N K SIDIAS Q N D C YV G F V * N N D S V N K E Q Q QNIE T R A L L Q G P K Q M V K C R G A Q A NQIHIA C V T A E E Q L E S W Q L L A P R R A V W Y V G E S D P S V A D R P V A Q A R A E R F G NAIL E N P D K F K G M L A A E A Q R G N Q S S C A H R L K L G A D E A S N V QKP W LIRIQ R Q V GIID E R K K Y K V S V L W L N Y KEI5DI* G E T T T Y R R T Q SIA V N L W L N F A C K L V M G QF V A H G VP G L W 40 G L G G PIIS V S F G N LWA K E S K0- Y E V E F N C Q T S W E E Q N Q P D SKIY EIV E ESIL S P M N Q Q E D V P F 9 D V S E R GP S W K R Q N A R R A L V N R E N E L M V Y P H F S E Q Q L S Y 6 A 4 L G A T R V E Q N C E K A Y S T A7 L K Q T Q T D G F Y L S Q P A N A E D N ESIM P G K Q E G A L Y G S V D AGIE V 1 M R DEID L P S V D S F V N P T R H A0 Q N A Q G2R A Q P Q H Q D T Q F D A Y T R K T W G:.K H MVIA K C E E K E S L GVIM L V T VPRIE K W V P S F A S F K WLIV L R S D R D D D Q F S D L C o K T A Y P D H D F A D L L P VNSAA E L Y W V E V P T H D F V Q C T N V A S L D LIR V G Ktekco 1 2 3 1D4 4 4 vy9e- - - 1nrysO R G o p _ TysRysZ 86tty 2LG 2 - p C y _ T p _ R 0 L-iy 47 - T 08 A 2 S G 3 G 1 M L 21L O P E G V D L M C D A K D L EP R G Y S S E GP A S R S A S V S V V RIV S LF G P A G K E A W E E K P L TIQ L A K E G D V G T F L D L P K N F A P V T R F R G L T V S L RS H T G T P TEIN N H K S L W R V V V K KIR D L R Q D W P KW V T G K A F T L L L Q A A P S K E G E G A G W T D A T H Q T N S GS Y M E K P Q N LVIW S T A N T P E T N L Q PYIT K R P Q L LFIL T T P G T A Q D M M L S K E S E D D S S A L G L T T D L D T RMY * E R C R S SIS L R T S SIT A E W P TS D P E Q K V L M F L R R FIQ S A EDA F G Q L E N N Y Y R Q F T M W P TPI IV A S G N G H Q FINIY H P D G S A N G D G K R V G V L R T L N R QP Q A N T L L E D Y D L A H R L R L E 5 L E W F4 K R TRIS N P K T A E K R HIIK G T H0 V L K Q H L G A N V H T T R F V V L W S H G P C A L0P V T L L C WNIDRIT Y *-MIA E Q T Y N A L R F9 G Q D R S D T T M S Q L R L N AP R L W E H T R R Y E H QP 6 T L A L K K T L R L H Q L P EDIC K L S4 N D T D G P Q T A L V K Q M R M F C L T E E 7 MIIRIR D G W E G F H L H T H Q P S T Y N T D Q L T Y ARIIIT W P R A R W K R K 10 G E S R K A N K G R S C N L2N L R S E D D V A L T K TP:IF V R T Q K S K K E L C L L D.A APIC L Q G D L C R D T S K o R D E N A T CGIG D P P W A G L K T TQIDS A R F W A K E R T K Q K R S A H FNV Q K EIP E K N E F C V P L A V G N R L M L V D A N LNP T T A K Ltekco 44 1Dvy9en 1nr- A R 86o LttE D_ T 0 L 8 A B 6 - 21L L O O ; P;P G A O G R P S E H L F A K RQEIE D P L A V A E T G N N E N IHIM L Q A Q E V F G T D D Y R E F T VS A V W R Q E M V E E N A G A D Y F F E P P V L KSIL R E P D L R R A L P E V S F A N A A V A R F N A S A S A S RAIHIA K V E R E P L TP T Q V R M R L S A R QL LPIT A A VDIH V T VWIS R R A S L V L R R V A F E D S A S C H E R C E L RRS PIN L D E A W T K K K R L K FRIV D A T KIVES Q N A D L D R P L K E P Q A S L G AIPIG T K P R L V H K R T CML S Q V E L G T K S S E 5 S V L Y Q P V L T 4 A A R E C K N DVTYINIS M DS W K M H G R L W Q K RLIV Q L E 00- MSMIALIY P R PIS Q S Y S V T M V T K R F R L T G E L L E P A T K A T Q S A G A A E T P S G R S C D V L E P W A V H F Q L N G T R A L H GNL KSIQKIK 9 G P K H G K Q KRIRQIL V FIL L G K64 V D E G W E D F Q R G E D P A H T R K L L K7GIK K R G V L Q S E A R K V T LVIP E N S E A T L W H V F K P A V D D Y S S N 1 S M E N P G A D P S E P V E T A H M Q E K0 T A2V T S S R H F FAE C E R T T R Y F L E:.TIA A P L A R GIC R T E F R VNIE K A R R E T G V S T H F R N A A P L L E Ko A L L G T E S K K P T P F T LFIG M K G V A V FRSICPIEP G D D R R N S L GNP H Y L S S V F T Y R L L Y V A E S S V F M D D L A A QKItekco 54 64 1Dvy9enrF 1 - R - C R 8o L nttE A T L o T 6 _L- E F_ L 08 A B 2 u B 3 -a21L O P R I Q G S R G A E K D L F E L LQIR W V P V G R N D Q E V K R K P E QVIC G G G VIIP K K V E L R V L T V K V L L K V V D Q S N Q R C G QIY L N S T R Q L ALIA Q D H T S K I Y F T V Y Q S G N V D D Q T Q VS D G D D K F E L V V Q N S R C S M F V ES N LIAIL D K K Q T E E W S L L D Y R YP N KIQ DRIVIIE G L R F L S D R YTIK E T A N G K P HQD D T D V D S L D Q L N K P P K K G V H MIE D P D Q L S E P L R S H L K L E DKIQ R V L Q L ES A E C G E V M KGIL 5 N 4 S K P D E Y T W PVS E L H Q E N S YIR L V S R L R S D F Q G N P G E F E S M A 0 KRA K Y V D D E T W E T A KHIRIR L T R G M N W V D S H G L G E L V E0- CI9 V A V S V NDIV M L T E S KPE E G G R R R K S GSHIR H V G TSIKI64 R K Q KKV V M DIMIR T S LMIF E K L D Q S TRF R E V V E QP TP TP 7 C A H RE1 S T SIE E Q D F F VS C E E E F V W YIT Y K Q F S S R Y K Q Q A W H G P K D S S S P D V S PVIA T L P N L V V C S K W S N L L G A Q L E P GP T 0 S Y Y D K L T G Q T P L V C N V S D D2DKG V T L W T G F G L P N Y NAE T L:.ATISIE R C DHE V N EIS AS D L A K P Y L W E V M V TIS K L R S P H V o K C Y L G H C C A K Y S L L K D D Y K K G N CVIW R S N L Y H L F L Q V S K K VNFtekco 74 1Dvy9enry1 s L 86o p _tty - V R 0 G 4 8 A 1 V T 21L O P L W S P S S SID VSIV P P Y CIIQ G N V N Q E L E L L K YIL Y V K K L A E R M V P V L E S Q K L L H N P L N K L PIR E R K Q E L A Q ARIT P E K E A E K K E N E F L M PYLIIH E H EIT K C R V L W P SSQIL S T K A L L D VSIN Q PP WEGRIT E K K Q P Q K SIKIA P A E R H L T L C N L QEIC L P E Q S K G K S D R L N A T R F N V S P E V Q H L K N Y G H E K L F A Y Q Y E E K P F K G L V G Q A L S D L S D F K R K N S V Q RPIS R E A E K V Y L V K E S E L L W E W A M A D A D D E E C TVISIL F L P D W E Q F Q P G N M H W E F R V G G F P NTI5LP S D A Q L V K K F T L N KTIF Q V R D T FIR V A 4 R D D E Q E M L D0 A L0V G P P RTL R P RIR R L A G F T G Q Q T FSIDIF T G N A R H Q G H Y V S R S E Y - L N E C K T V 9 K M K F M L G E L H F E F V H W C V Q D D G T F S KMP R SIL D L G F P T K I D G T T A T H HCIM N Y CF T R E Q 6 N L P T T WTINID L K L T K A L D L P Y L 4 C V T H P S L T L G K P S E L R N E C V N R 7 L K C F C F V T R R S L G P R L E A T K E R L 1 K N V 02D E Q E K YPIK F Q Y L P L L K L K V R H T Q E L N V G V R P Q T A R Q E R E S R N:.Q Q TKIL K L G P F V L Q L E WS SL P R H P D W S D R A E L E L Y S K L SI IF G NAIo M S S V N N V Q K F E A K S N T N M R F S E L R V PNK T V V L V Y A W R N A C F H S L S R N Y R L R G Rtekco 84 94 05 15 1Dvyen-r1 o A I L - 9 _ysLysR 1 G R 86ttVF _ -iR H 4 p _ p T T A R y V R y _ T 0 S 11 M L - 2L- 8 A A L T G 6 V T G 3 21O RP D V G E E S K C P E P E N L V L W E Q E L G H N Y D P S K D P D H V K L T E C P P L M K DP LS D T D V K L DS YS D S S V T V Y E NS G C N S D G K S L D LIIL L L S R C T L N N P G C EKIR F S C Y R H S G H RFIG N K T C R K Q F N C D EID E D R KE T SIGR M D T F P V PIV L D K P Q L F K A D G A S M F G R S K F T TS KQE I Y K V R H W G W R V G P P S K K N N R T R C N E S R W R N A K N T R E A L A 5 V N N Q D S L G V E D M V LKIAND AIR P W A G H F S L L DTIA A N D G P L L K L G K T L Y Y K G E K PPNIV H D N 4 S T L Q Y R A C T V L G L E K D P E M V00- D R K G D C K Q M M K E R L L K FPIK R V P Q N F V P R M PNIV S K P T L L S P 9 G R F V S G P W T D P 6 L V T E L R F K E L F L L L K L V M GS S R G S E P S E N 4 N V V R L Y T F L D P K K L T R L T A L D K V S T S D T K V T H P K S T L G 7 P L L P EPS S C S G Q G A D N G L Y S N L F T L G W K N A Y W PEIP GIP S AYI1 Q Q E F S Q Y L F K S E L C V D E E Q T02K Q C V D N V F G F G R D K Q Y M E G A G:.S F K P S K T D T D T F P V K L KP LHIP K K G K H Y V K R E E W G L L E P V T W D E T Q F G G D A K C P A V F M R T o F D L Q S S P E T Q A F K G P S EIL R PNM N V F Q K W T M R E F A K L Y P K T E P S A Ttekco 2 3D5 5 1vye- - 91nrysZyo p _sa R 8tty 4 R p M 9 - T y _ T 6 3L- 08 A G 1 M L G 4 d 21L O P D V K P P L QS Y S A P D K V E E M P N E V S T D A V T K P A FP R D C T K D R V C S L V M A R T K G E S PF D K E L D K AS G Y N D DIT W M S P Q K VVIN A D P R G F T V L V A C T N PP N T K T N H S R K F SS D N A H M Y F K R P C R Y V V N KQ V R AIR Q Y ERIS P N F K V A R A K T H D G W E K G N G Q H L Q L V E F D S R L F F R Y K R H Q Q T P L * H A A S L A K LPR K L P H R R F S A V R R K S E Q VIH M C E R H F TMIV D G L A D E G Q NIF F 54 E Q Q R K H R P S Q A T S N 0 A T G Y S T PF A DP G V C R S H K K C W ADIR L0- K E E Q E L Q V E P L SIV S L K R L V F T LS P E L P M RIN R P P S E TAIV T N Q S C H S E Y V Q M 9PIN K A G Q D A S F G Q C T P V Q V64 N V E A S V L K P V A GP7 H Q PIN R P K L P M R R D D K L E Q K D D V D K Y 1 G A K A M DS E L C C A D S L G E P S R E 0 P K*T D D H Q TS N Q L L S E L2R G Q T E T Q V T QIH Q L S K S P D R Y G K H V G R M VF:IL P C D T A.P Y F Q L S G M T T R SPIT N K L K T V Q H V V R Q D G A R F D L F K Q o KIIG A GRK A KIIILHIS S S R V V S L R M K A S G R S F K L Q VNR S S W S R P E R E F E K A N G H L Ttekco 45 5 1D5 vy9enr1 S R 18 V _ - A_ T 6ottR - 2 - R L 3L- 0 E AcT E 4 8 A N 1 S L B 7 A 21O RP NP F G K Y Q E T E E L E P N A V P P Q D E D Q E W TGIV K PIC H K E W M L L Q E Q R S V L N L S C K A W V K HVIL V S P F S G V G L K G Q LP MIDF G L K R L A Q V K E V S A Y EIIV R A K S T S A L P S Q D K A V GS N L H AQID P D K VAYIF RR F R M L A G L K Q C R Q TSIM D A Q S V S S F E S H H K T K R DIQ F E DPIL A Y H V L FSIP AID E K SGIR S V D S P P E L H W G N R KPIR AAIV P R L R L MV5 G L H S H G NIA S T D A S F T Y T N H S V V L R S Q E M 4VIKP K Q E V Y E R V Y H L N A D A S P E R V G R K R D F K S S E P R A E S Y D 0 R0- A D GTL V WIS T Y R I H NDIA L SVIR A S E R A D P W L N D A V H Q L 9 W A K L K H VRILAID D S A D R L6GIL S Q W H G FTIV E P Q G T Q A R ARIP T P L L V LS R A M Q L Q V P N Y E H E P K * V A R QAIR L G SS G G K 47 Y G S 1 D L S L N TKNIKID E P E D T R R H K Q S S E Q A K H A MIIV T TFIF 02TS V A R F T E M E L K L C K R L W Q F F D T V L T Q R P H D R K N Q N Q P V L N R T T P F A HLI:.EKIT L L R P Q A L H HRo V E L D K T P D RIS V Q A T L K P R T D L A T R Y A N N IIA L L D E G W A S S P K L G N P A Y D E S L V D V A S E Y E A P R S E Q L N V E F E S ANS Q N D A V L K Stekco 6D5 75 1vye- 9nry1 s Z 2 8o p _ R E Rtty 9 T 6 0 - TRIL 08 A G 2 M L R _ 21L L O O P P K T K A ES E GS KS T K T A P V E G ES A T A A A L RID E R AS A M E R T Q A M D C S E K D C T V A Q KIDS RL V P G DID VS SDIH A M D V V SP E K RIY S * L K A VIF Q K L A Q D R G T F N V P V L K P T E S R M Q M Y S H L N D H V K T P Y V V C Q NTIG S K A F E K Q C TAIG K P R V G D ESIQ C W P L L T P D E R S T S K L Y F R L A D D A C P GS R K H SF V P L S N E G K P E A G Q Q K V R G N E T P M T G N H PRIG A S V T PGM H Q F K GEIA T N S V G S L F EP T GIQ C G L EPIG L P M H L T V FI IF 5 MIS A C K V Q A E R V QRIQIL K T S S V T A H K R E W E N A A L F L P S Q V E D H L QS E K R V N L G DQH I S VIPNIR 4 A HIA A C H G D S R F A F E L V H E F A L 00- M T A A Q R K T S L Q T R G EPILY9 M T T A Q FIY P K F C T Q S V R V S D Y P T D C E 6 M P G E F T C E MLIS L P F R N N H H EDID D C P Q Y SYP E YIP H T M D N 47 Y DYIT PFIM R Q D A F V E A E P M Y V M1 T S M SRIQ L D L P P T Q KAP A M L Y V N V H L F G L R M AIH E P E C L L Q R 0 Y F E Q E V KEIR Y H L A VS P N R L L M2H D A:.P L Q E VPIN K R A E R V V A N QPD E GIP V F C E E S S T A K Q C V R V R H L W M V A T R M G TVIL F S V D P N W T o S A K Q D E A N D V F H C D P V L KAIT SNG P R F V G D L G Q T G K C Ptekco 85 95 0 1D6 vy9e-nry- 1 s O Ry- - y 8 p _ Tsp RsZ 6otty 9Ly G R p _ - R 0 G 3 - _ T y 2 T 8 A 2 S G 1 L G 8 M L 21DF DP L Q L L P A Q T L KS K L A DF A Q Q QSP G * W T R Q F L S V V R G V N L K A T Y L L E E H K L D P Y A T AIS T Y S N F L D T R P V G F N R L R K Y E F S F G F A A L V G P L K FS GV F R G E P L D L LKITP R Q Q D Q S R D EYISS F T G CGIG VQIS P K S D H R L P E CAIQ K M T D H L M Q L W V T S F Q Q N R A G D V G F W P F P T EQIG T V H R L H R L R WPIP G K GQIR H P R P L L N R VEIN G D Q R A P A R V G D P P P K E K E P R S H K TCIQ K H V T L P N T R E E P P R L N R R R L G E E A L 5 TGI4 P T PP S N PRIQ K L A * V S V A L V L E S S K D V D F L Q V A V S F K D A S 0 LGIG S E P N N D C D K V A K P P Y T K F S W S Q L S Q S D W P P T V Q P R GF M D0- P 9 W S LP R N L P W D AS A D S E M T R E K P G S L L W P D D Q Y F S F L S T KGI6 S A S 4 D S D EP N W Q C W H R A D G D V L S Y N Q G D D A N PR7TIC T Q SGID D GIG R K M P Q R R R V AS F G L F H Q K 1 A E S S L P F D Q G L P L N F Q L P N R T G 02 VIL Q W V P D R P A S K A D Q S S E K H R G V T S Q L H GAIT A L A R K R R R S:.K E G FLISP TS L M L A P P Y G E A R K K N R L V V G F S L F N N T F D D Y Y G P o A TMIY PANE S F FIP D D D E S P A V E E L A T N L F L F A E S L K N A P P F S R P G E P H Y K L E E L Vtekco 16 26 36 1Dvye- 91nr1 C I T Tysn 86o V _ R T _ L p A -ttR 3 - A _ y _ n R 0 E A o T P A 6 T 8 A L F M M R G 1 A L 21L O P S D R F K L L E R K P L W T F P F D Y V R QLQIR E R D A Y T V K D E R L V S G V L P H F G P S L Q VS D L HS DP L L E P L L V L L P S R M F T C K D GP E V K KVIG Q S V P E M L A E D P G EP V T FS A E R S G H M P T V R T W V K A R C V A L T L F GG D Q R K F A S Q H E T E R M G V N K R N L A Q K L K GST C R A L LSIE EPQIG T D P A L SRIA H N R V R S T DISRIR T P E P G K V K L L L L W G A V L F Y L S S T S S F Q F V V P G D C F N D A G R P G D R S G S G H A P S S R K G E E 5 R 4 G Q CIT G Q S Q T A V F W S S AS W AP T DS S 0 QGIV N W L R Y F E S K A G A T0- A R T R TS D G T D Q S R V G P L N A S A L HDV FRP D Y P A L P A P PIE W RIL G CPIE Q E G S V GIC S Y HKIS N L K K G HIS K A S Q G G L G L A 96 D 4 ESIT GF V F T V D H GDIH R 7 S G K F V H LDIE V V GRIR L E G Q D W R GS R G Q Q R P H V V A RFITIK TP 1 E E VSA V L D P T M R S E P L E V QF F0 G G HIE R F R R P D H M2P R A H G V L R G R R K G PS M M GGR G D RIT RDIA K:.LA T I P A Q A E C D L C P A P P L M S H D V S V AEIP D F D Y S D A G T R L F T L L A N W L R S Q S R V L T A R Lo P V L R P L Q C R G R S S T Q T A G E Y QNS A E A L R Y H Y Y M L Q P K V A G W R N P Q L V L Htekco 46 5 1D6 vy9e- 1nrys- -o p Dys8tty B R p M _ T y _7 -cR 6 T 08 A G 1 L G 3 A L 21L O P P Y K V E EIF G A A L L R E V E E R V A Q Q R DP A Q R R P K Q K VP R A DP * SIDIN R L P L H P H Y Q C A D T K K P P C D A V R G N T L M S D T S Y P D S V W C A M F RS P N N S Q V A L H LMP QEIK R L R N Y F R T D D W S M G K D D L Q T AIN A A R C Q F VMIE R A W V S P R N K S P EGCLIA G N N S Q G R R A W A M K E C R Q N E R S A S NSIL T L E NKI IK S E H D G 5 E H V T L K L Q D F R N C L L A DS D T L DSIV A P A DS C W E E V S N 40 Q E K Q R A N R G S F H R E N D R L V H F WNG R L L A S R E K F S A F S N0- LF K K K K L Q 9 G V R Q Y H Y P A G Q R H E V Q N M R V R V AIT A D L E L W R G L K P 6 L T L E L R P P D EIK S K A K H L V H A V L LS Y V D L E F 4 V G R P L V R K E Q C S L G G P Q V T T L V L V V E T P A H K K L A E DNI71 V R N QIQGQ D R K W V V Q R S D Q E L 0 E N KGIQ P NI IE ERIA F A F D P2R S K K N LPIP H G K S E A A V D L R N T P V R F N D E M R R Q V V L:.E N H L Q K K D G A T E E Q T R K E L N L H K L M Q F P C A M C L A Y E F L V S E W L DRIS V W K V Q S L V o Q W E R Q D H E G D T S L M Q AEIRNK S N S N E G L G K D Y E Y T F A C R S A F Stekco 6 7D6 6 1vy9e1nr- n o L A - QttE _9 - R L C u T E _ R 8 4 T 60 L 8 A B 3 F L B 6 - 21O R L P O P DP K V V L D D K F SS R H QP HS V E P L W G Q Q R F L V T E S C H K D F L A R S A H C T V S M KS H C G F L P V C A S G R L W G G T D A T P A S T V V D L A K H K V I T M K N S L K N LP R R EF G G T D D Q V L K Q HS A E LS K E SS Y SC K S SP A D K N R H V K P F N C H N K A D A Q G S K Y T L N F E Q E TP S S S E E L L ERIS Q T S Q K D N Y Y Q K L C S E S G S V V S W G P T E E K K R N P L R S N P S G G W D E E R K P A Q V Y N L G N M M R S S Y T R P R S T G SDP Q V R E DGIA Q YGL W R MIT L K T PS G R D Y Q LSIS G 5EL I V M A S L G L N T H 4 A S HAIE RIS V P E L Q T S V N V LQIA L K H H L N K W N M T A K M F L E Q T M N D DDL A A N V G L Q A P D S L Y L D N N S S ES N R N SSIS L Y D 00- L H S H S V PS TIQ Q D P L T V M K HIIL N N Q L G G T L V KSIF H G G G SED 9 V G L R P R A R N S Q N LSIV P K S FIG6 D K C P D R K A R N D Q K KTIP V S F L Q Q4 L P N E S F L N LPIS H G F P RKIE N A7 M FNIP V H K E L T A Y N F L P E Y T E K P1 YEK K T K E D S D S D A F PIIF T W Q P0 AIC L H S Q R P W Y E W K A F K N Q L G V A2:.K L E N CMIAIR L T L C E G T H Q Q R F S F N G Q KHIR L E T A M N F E N A E Y P S oVIK K A A H R LP R L R N S G S K N C N K V QP L Y K T L T Q E P P R A A P D L H L VNK K E R S M G F L P Q K D E Qtekco 8 9 0D6 6 7 1vye-nry- 91 s Ay- p T RsSyL R 8 p _sA T 6otty _1 T L - y 63 -iR p T y _4L- 08 A G 1 G 1 B L G 6 y 21F S R C G P P L F T PIF K S P G K P Y D P G P L PIK F K A PIKIK K K K G QIKID AS V C T E P H K S EIL Q V P V S M K G A Q Q V D E RPQIV R A E DMQID M L D K K T L T Y D K E H V S Q D TPEIL N Q M I F S A D EDIG L E P QIM R E L S DEIE E S R E P V E E S F R G F L R A N F P F Y D R P L E A A Q T A T P TKIVS R K K L G V L K M Y R YEIF D C R * D S T H L C S P A K A N E T S E V R S P H A V H L K GDS D N Q V YFYIG K T P R K K K F RSL R R P S V F V S P R T 5 A A LIL D V PDISF G V K KAIII IS Y K Q A D P A E P R P E R L L V A A A 4 Q F D L K N F D A H D Q F A E E FEA A0 N C A L P L P L Y G K K RID N G V T S0- P M G A L A K A R L D H KVP GIF A H L W D Q W Y D A P E L L A P G E G L K 9 R C K N R M L K E D A K T H Q D A E R T6 A R T Y L Q F F FDM F H A LAR M T T47 R Y K D A G ES P H VIL D L D E S K D Y K V A V RIR T G M R T P P D G L A R 1 L K 0 E E F L L2RIIF F T WEID K VRIQ F E K F V D L K T S S F V D S P R L H F G A L P S R E D S R T D E G QPIM K K S T R G R F T T Q T E S G P N G S S R:.G D P L S R G G D H S K L AEIV V L E H E G P D S KPIP L M A R G E F N E G o H S S L R K LLIL T E A E R T S F T ANL N A L C W N W Y V S S A P A T T E Ptekco 17 1Dvy9e-rC 1n ysR 86o p C Ttty _5L- 0 i 8 A G 5r21L L O O P P R V L L W N D R Q A L G Y PMRIT A E N M Q Q V Y Q R QP Y L N R R S Y R A D T R F D M G R R Q G E G P S Q L R F P P Y C R A T Y D M A A Q H R G Y Y DP T R R C D L R R W D C L V E Y T A R S R G Y D G T G S G A R F P T A A F A R H AR G H A V Q G E V G R E A G P K K S L R TP K A V Y ATIS Q H L G RP D L QSKL I H A L E G VAIDLQ T P H H E S F F R K R W PIN W A A P L G W E A V R A R T E L K N D F KP L L N D G D G R M C G A Y D R T N T V A L P P E R R C T P A A V S K V V Q T H T T TP T T K T D N K F D TSIR GLIS V A N V R T T TQIT P S P Y T R T D D T V 5 L F G S L P S P D S T W P N A M T S T D H A4 P G K A VDN P G M W T A Q S R S S M W T K00V Q E D H - RSIK L E D N H RPID T A G A V9 P R H S K QIV P G E F F 6 A P E A E KGITIL T S G A S K R K D DSIV A A T T L R V Q L V T WGIT L L D A A Q N R E F G E 4 E R T PV7IS EPIV P N L G A G L R G H R Y1 G G P L M FEIN A P H N G G Y V W Q H Q H M L L V P * R C D F HGIR L K Y T G D Q 0 G E2T G P A E D S T P L K P L G V S S K Y N D R A L T PP Q F P P D PP R G T P T R D A:.D V Y V P F F A D R T T S M R K S Y L A N P E R S D E L L V R P T PNIP K H L L T E o A D RNN Q E K E P P S H H L G L F T D L S V P T P R D L A Q N T G R S G R W Y N V E L T P L V G A Ttekco 27 3 4 5 1D7 7 7 vy9eanr- - - L - Y a R 1prF _ysR 186o LttE D T V C R 2 p G T TNIL R y _LB _ 6L- F _ 2 - 08 A S 1 L C U T G 2 v 21L O P G D P H C E A R D A K F L H L G D A M K R V G L C S H Q Y A C C V G M S D D G L G V P A A W R V Y P G R P G K E R V R W E A A E R R V T V A P P R V E P W PP V P PS G E R G K G E A RP G Y FS H C L E D A M A P T E F G A Q E V A P L E K K L P SA E E A A D A P H S V G Y S E F E Q A P A W A S EMK A V V T CDID T D K G D V Q G D K V V V Y V E N LLIA SIR RP GAIR L D V T S L KPIV A E C T R G E G F V S VIT A D K R R Q A E F A C R G S T A Y Y E A S T M LIN E T V P 5 S 4 E R P G E T C D S R P V F P E R S D N L Y D N Y M T D G G GTIF 0 P H M L GTL E K L K S S L T P Q G E D LRIQ T G R P V S A FID E VTT F P L T E YIK0-9 H G C G VAIQ V L6 Q H RKP S E VIE L V R A L Q T K R* P H V FHIN L S A F V R T L 4 R V G L S R R W R N C Q F A G Y L L F P L F V P S A G A M S NRIE T 7 V R R E F L EI1 E Q P EIW R T K K S R K G E R F P S D F A E DDN I TP L 0 W W V V R P P R L T E Q R F V L A D E T A E D L R K A S K A S Y N M F D T G S S D2R E E D DDICLIP G R G A L F W D K F P E T Q H R N E K T KS S L S Y F:.Q S A G L E VP V K G P P A P P T R DHG Q Q DPRIQ I T LP A C F T L L G o T A R K L Q H Q R R LNR R C P D P A M W E M Q L W T K L T H A A L R T P T M K F E R Ttekco 67 1Dvy9enrI 1 H C R 86o 4ttT A T L 08 A A L _ 21H I M C C M V R D H P S G ITGIT AIR D T DPIL L S E Y D G K L E A N K K R V H V N T R V L G K G S L K KL P T C H EYY V A A Y H d TteVQ CNS EDIL V K K C FIW KicL L AADR T E E N K E A K’reQMRNIP L V E A E P S V G VaP DLVWF E H Q D W Q F Y T V E V VHI5 h K T W T R oetNRDIS EGV A V N P DRIQniEK KKTL P P D L F V L K K K K E hytE K N S P V E L VHIL F A F L E F S E G D V T VLID L N mtsaitALENV W n GKEIKYE ER S H K L A Y E Vae sGD KS EE A WSPIK V ENIA E T F DKN Ana ed n DGQ ES G S LS D N S Q V F E E K P V V H VIL F PsID F E K EmC T D A G A Q RQIKeai osS REIAP NLIK 6 VSI sn % o S QHETEN Q 53 P P G C S R L T L D C G V A N YLIN L G S R Nir e99psEES A S VA LVfY TIp RGINT Y I Y ADIE S mrn AP KP KLoG L A T YRS G D V L NIT S Y V R S L E E N maR R P N S H N V G K oso e,artQVVQEES 4 RES N L QKKKM 11 N A K P Ec% V E G L L L F K A YMIR E L K G K A V P V L E P K K L L E N I P NKP L P D L DEIS G F K D V D E Y H W E R opf09 n S q GDE K KLFYIGL A R L M V Q L So,otGRIER R P F S R F S LeesQS ELQ K F V R E M C E E S R u _ EK S A A Q H E V Q G Q A C HLIL L V LhtT %5 a L A S K TDQE VKR 5 P H 4 E D 0 D0V KMIA L L S K F K P K K V L L G,- W S R D V ALIRIY K Q A H PstL’8rA NGN 3,of_ QNLNIE 2 RES KS KVS9 D S TED L PLICFIned %sreASSIQR F QV 6 SIN G W V YP M K A T4 T K A S A M Dmn 0ecv EA D RTLQKSS Y 7 T E D L V R A L E E E E D NNIK LiG R da8,n irTAGEF F D T N T A F LSF S o R %eD E F A E L E P102P D E L Q KFID RIW R H Y D b T L S P H Y K K L L 5 u 7q:.TS L R S S M T A K T YSIG L Y H Lme ’5, es Q EDO8o THIY D ADND M M C DIR K G L S R G D F P Ve% SIN 7 V Re2tm h 0eos t7trev -kcotsonI s aierY L A 1DdynleotD a:_2 v 9 91nr ]7 psgCel e -ai86ott4e0rrniv b ma po R T 08 A0[oc aa h T N C L 21D L L A MF M G E R D D E DP HP L RIS GID V V T Y G Q Y EP NF QSSP Y V N QP A A RS T* NL P R QK TS S L AP KHS AL KV GL KQSAP RRP HP TQ K QERFNIVVVQDS NVS KGLVVKGEELS AQ VN L KNSIR K Q S S ED E S LLT EL MQRI ITGP EV G R M L ATLP S KAEED M P KP F S NP TF RDLYF K T AMAE VNL G D ALLG EK VCASIIL T A TAITQ VP LKKDMS KEVR K WP DVAKIEGHAMHKDAIS GY GVG LRNHEGS EQ TF KVRDHERVSVIEMLKVEN T YNVL QF S F YTGF AKY YD R S E AV T LG 5 AMRTP KGKIN E L EVAIDN HNIVA VLIE K LHKAEN TS DGLF ALEEDF P P ARIL KT A TTNKWRES KF 4 LL YGG LC S VK ENA QM S P N P S 0 QK LL SIQGYLK F TP F K GN F MKL S WK E LN QGS KTILDAP Q V AP TQG G DLINNQD L RKT LGKLVA KS0- G TAMMNV V VYP VVELF MECLYQ9 RIVK Y P RRS QS NVVGF QALRDV Y QKKHF E S AA CVAR F F RKQIC EDADKKSSITADE RD P TRS EQF 64 V KAHK Q T K N R 7SIT E KRVFNF A H P KTVGL A ADYF V NQ V QKAILQ F G LLWF P S NVS D T Q Y P K L G A N F E G W A W E S T V C H E D H M Q D M H Y K V R P E L G 102:.9 0 1 o 7 8 8Nte- -kcS -iM o O G _2 C Z _ _4 1Dy2 0 7 v9e2-3 1nry- -1 sy8 pRsyps6otty R pR T y T y T 0 G L G 8 A L G L 21L O P C YR YD AC HIS KK C AFFMIHH KA RD DK QF L AS NP WW ET S F PIG ES S Q TL VV LK YM NA AIT HK AQ S YA WF P H TS KG VC LA F N ME LH S C E EH P N FLIDG DQ NIQ P E LD P E HP S V NC HK AIRIIMG V QE A GE LQP DY P ADM QDEIQQVL F P GVL DS VF L VS L AAQ RVMRCS VRMKTP LQT D MTNNEVKAL KVTME Q S LTVV RDMS EL A QIILK RQTMITLS T EKET LGSIS S VDCNAQGQKWAP PS LTIT S ANARNNIH LLAGNNTAS RC L P LRRVR H CSILEERDIK KQEDKL S P CS AT LC HYRKY P PSIE E GHKAH ETIYITTG VTL S P WP NAKEGR EV TAARP E TPVIELVFP VAL P EAILLVP KN F K GQP H KK S LKQK TEY P A HT F VHEL G T RG VS 5 D 40 AF TV GN L MQE VT RGTP GP PP DRIE DVK T V S R KDLTQP F G D QHK F Y L GW VL G F KF GDP FIIAIQF S RLAEIP P WS V K DH R VT P YL VW A H NLGAKQF V0- VP 9 GRLIHKF RPMIS CVL T S NHSIP DF VDCID YIIKH CQF K LAYD S LRRV 6 NELS TWP S KEQIS H QEEGP LGRGMRP VN LP D YCENKMVKAL LKDACKI4 EERFIKKE KYTIS GLVY P NLDNLAT TS SS F VVLRK S QVQES S AAGCIL 7 V W Q N Y K M K R T N E A L L F F V D N G T K T N E P R TIA S Q E L E R N E 102:.5 6 7 8 0 o 8 8 8 8 9Nte- R -kc iT M o M Z A L_ _ 1D- _ 4 4 vye41 R 1 R 9 9 T1- A -6 T1- 1nrysL 1LIyo p_sLys8tty V VR H p_ pR 6 F T T y V y T 08 A G V S L A G V G L 21L E D A N W S R PID N G D M D K L R Y S GP R SSS V V LFP G E W K L Q L K G V T DP N A V R R L V L H GP KIN KL L CLTRQD GQS G RMIG K R R N RLIQ V ARALRNS S P LHAAS EL T V HLK ELVRVNLID VYTNDAHA RWF HF LVKEF AGTLEP TRTKAEIIQARAKLACDA LQLL K S TSITLEAQAYYLCICPREVTRKFIQSTIEVTI IVP L RE E L R K DAAIIANVGKT S LR V EL E T D GHDANP F EP KV EKIAD 5 R T 4 D YDYK MALF GI0 R* T KRHM S G K KLLT WF QK AD D KS KGQNP NKSSIE A KQSF YD E NMQ S EKKS AVRALALF ATILLV Y REA0- WVMIW AVRGEEWF DHGIA ATQW AY M TTAP G LF KLF P AE Y HM L S Q 9 G TDF RS RE VVA W P TD M KE DLRP VQFTIS KYK N 6RIY AQ HLQRIA R V GE AAS GLDA ED H A EP KVVP YS T LWTMFFIV P F N F E NAAHLDAIY L E MEGE C RL ELS GADKRPSIN 4 TR LP Q L AEDE LS N LP P LF R H RK S E S R L G A R A D M N Y L A A H 7 K Y G * R K R R K D R M L V W E H C A M Q D S R102:.19 2 4 5 o 9 9 9Nte- -kcdaR M o M T Z _ L _9 R T 1Dy3 - 0 ve4- -cL 9 NS2- _2 1nrys1 So pR V_y2spR E 8tty T RA y TR6 I 08 A G L E 1 G L R 21S VV AVP TP K A WFEIF W GK QS RF YK ADKIGA V VIF TL RH AT AY AG HG NV GA CIK K GF S P HIG DV KM LD LL QG RW G EV EA LF S P VW CS RL QPILIT GQ S L P E S Q KA KP YL LHIEQ AR EA HF MF VQCNKLWRAIIIIYW S AF VAT EYLKGS P EQP LKDIQF EGRDVC YIS EVS F Y LE RP AG RVRIVATIVG LGF GA R A NLGAVEL D EF AQ LCADQ NGS KANLL VL HEGP YP VQVHAP V KEF A C YEDVGF LT KKH DLMEP EWATAL R TTAMATFLIP GRNES N ENL S 5 RTD 4 RRP RVLCES LLEAAKVL ATARG QIL LSILPIS GS RLP DVTVQDNP TKES EGRATIQF Y VLDP VDP GY GYLP A P AQIVAGWHS RER DRLLF 0 R -S VINLET CGTFTIALINRE DLKF KT E LRGWILYELF RRV F GR WV0IKDREGRQP HS F T S FLL* DVW S DKPIP KS F VLTWGLIP P V QTITT P 9 R 6 EDADLD F RE HGA G CEF L GLTL L KF P G S ARHTVDAA LP TLALTISS QT LYQS EQTK F L P P WS NL K AYE 4 AATIVHRF AGWHLKC GARLK L ELYKHLIDQVP T LKLAS LE7 E D T R L K L L C N K K A L K P P G V W L W R T A D D E S G K T E L V G G E V D102:.6 7 8 9 00 20 o 9 9 9 9 1 1Nte- LkcS - - O - M o _ -o _ R P M D 9 Z C T 1Dy3 G_ _2 _ _ B_ v9e2-1nry-8- 3 A A1- 1 sypRsy1MIy8 pRsp V Ts6otty R R pR T y T y T RT y 0 G L G AR T 8 A L G L E L F T G L 21A RV EV GA LV RP SIL F D RE E GR LE AA AV VL CV GS NS LV RV QQ VD DT KA VA KL RY LL AL L KP ME KD EIL K AP EIA KV KLIP T NP AS QIK L GY RQ HK S L VD LF QF G LA LA QE GA S EP DT LGW S S FDTIM L F S RLREAP TP D P S F KNPLRND F P S LVRFS NAVP LILRQARG MD S LNHKDTNLAS AT RHIF P P LLN CG LVIRA HGRS EMEGDY GADTADLT RGP AP CKGS VSES G I VA P RLPQIL ANAA S AKRWP F F KRVE LEQ K RMQRA E GIS RT VDY YLC K TL P S R EK ADLS VDLAPLP S P PIS GL ANAF F HD F QEVHF LLNK TDILP EA AQL P K D D W ARF G EAIDWWS S ER F P E F L K HD AF AKFIWR TVIDE ES VG L DS D 5 N GVKIA Y RV KS VGYRNL WS DLEVLR GQIWN KWIN V RRLDHNEGN DS 4 LM00KL AYTL LE R S DGTF TGVTS VP GLCEARILGYS GP HLCDGP DDGS Q - LK TV F AEPYILVA S VLLRQYV EQDIVRLDLA R L KS P VA S LDVMNA LTQKG Q AVV F CTE KYS V LKSRGE 96RIF * DVALQGYKF RDAAS RRT EKG A WVRIF 4 R KY HMS RGVNQKRAKRLIVLT C EIQSP T QF VL Q LQ AN L LS V V 7 R L A L YAIARY GRAP E GR E S E V V L V GT A R M E L G A L K G G E P S S L M L F L T P A R V P V L 102:.30 5 6 1 0 0 o 1 1Nte-kccA - -o A M_ Q T C _ 1Dvy7e3- _ 1 41- 91nrys6-y8 p Ls6otty R R pR T ET y T 0 G L B 8 A L G L 21L O P DD LF F T CF K F G S Y HV NSF A LD RD EM LF MV EE DIMIF E P LEIP M F D HS DFKIS R TM AM KC NR LQ KF RS YAP DIA CN MC RL G WF GS TM VR TR RY QA PIY LT EG NY KP EC NTF MIT VT TKS MQ GD G CD KP RP L S VVIE E K RKKDR Q S KWQIIKKT RDVR LH REGRAADP P VNQCS DAVYTNHH LPIS I CEDEGTR EKP RF EHTRASIR LTP HTD Q WTCRTRRIQKA KHILAIAD E F P F KRE Y P N NTTS EKQVS MTP GDR CCF DRRS GG GS WS P VPIVS YKIH S G WWDTRAS P QGTAF LARRQEF GADRDV L LVCGDSP 5 QKFAIERCMAENVKV 4 V KNP N TP AANT LAKAVP L AF RVQLAE GQTS V 0 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DTDA T RDNQ E AVRIRL F E QIT LS ML7 E 1 R LP0 F AIVA TAR ETTHT F RQDD ED DAS H DYK F RK A P T2P ES GGIIVT VTLAYAV RAA T P GLL F DV RR AGRNRDLR P HF NQF KVDGK KRL TEALNM L ARQVRKRGN APSP NF KL H S:.Q P DS RAVE AVTYG DL HE P S V Q GYIEIF NP G L VF S F V T N AD S VIRAVLAL P D G T A G T CAH P TP TY F R QR YRVWA P CVT NNS FDIR N o T Q L K A P R K G T N F K L LNtekc1 o 7 2 5 7 3 5 7 4 5 75 1Dvye-nry- - 91 s ARyCyZR T - AR 8 p DTs_-s_ L DT 6otty _Lpy CirR p8L- _ 0 G3 - 2 T y 9 E1L- 8 A 1 n G 6 C L G 1 M B 2 n 21L TIQ TIK QIIK R TP L E N G V S T LSS L R Q D LF EIV D K L N QID NS K K V Q G E Y Q Q L A EINF K KIIIH A FIAC VHAMG VNP EDDEYSS LGL LVIAVRL PWIF AT VS VS Q L P AEDRP S Y ANC T LMGDDGTNGP L T A R K S EKVP A D GLYKA S QA EDP TS ADWWQV W AP P HAS E S E AF P P QGYQKL DS HRP HAAC NSIV QVE YAQVIS L G DF NP ERP QAQ K ADQNP TQAR NRQLL VA TVYDLVTS DG GS QE VAAQAT E EDDMEF Y S GQF L P P F D QP GR P VD LDVL T * N 5 L NKIMAS S L EQRK EK V KDIAHTQLRHGLP WV ARAF Y GP EDY P NS GG YT G RLT VL 4NF V M KNIAKLTK DQQPIETNEP ENVP NICDA S T 0 LLY L S F RTL P NIE NGRK RACD AGS KS ASIVIARAS S QF N ENLY LS G NP L Q GPIQP WIQ QAATS GEEAF KLVLIQE0- KP 9 LC MVDKLAK VAGNTDEP QDTV F L EGAS ED A RLP C R S AETP DR R RM R DQEEP G 6 RKLMF E VRRAIILY RLLCA S HGKVGHLG HNVS LP P RVRS D VGYRY RRAEQ TRE 47 MAES AVRQD E K 1 C VDGKAF EEIQTITS G VS HW P TWEP ME GAV ATG TRDNQC D ETEHT MRF D NQF DTE DNMDA N P WQV KRL LQAL R REIF KKYGK P VP T ARV LAYA AATTL 02 Y:. IAHF E HTYP S V YRVWRQV K GYAP S TNGVLFP LP A EC RT VAGR R P GL NRDLR P DL S HHP RQRDIQLKA P CV A QP QLP AE A TYGR VL E K T Y T EF T S R R TK WCIDIA ALA o L A A G A P R K G T L R S A A R R W A S V P D G T A G T C PNtekc5 o 7 6 5 7 7 5 75 1Dvye- -i- 91nrysZR T -o p_ MysC_ 8tty 47L- V R AR p _T y C- R 6 2irT 08 A G 1 M E 1 L G 6 C L 21L L O R P SF M TITIPIK G HL S A W KVIS Q KIR F G P G GF QG C VL GP VH HT QA VD RHRIQK AD ED P KE KQ Q KM KQ R NF AA P EK S A S F SIIGD GA TIA P S F G VT LD KV TL AV S N S H AV VL VF QG NSKIQV S C ASIV RLQEWC GV LYKAL LIS VP RLQAP D V EDP GLYKALIS VP RLQAP M TM GR E I KLRF E AF P P QKS HR HAAC NQSVVEAIS GNAF P P QKLS HR HAAC NQSVVEAITA WIVTP QGY DMIQ Y VLDF AQGY DIQ Y VL T E QGN EDD EF YES GQF L N EDDMEF YES GQ TD N* Y REGR KKIAS LQRK K EDP Q N MS EK KDIAAHTQLV RNKIMAS S L EQRK K KDIAHT 54 S T DQKF VD MS N YIKLTK F VD MS KNIAKL0 THR RD P HS C A TLL NL S GF RS C A TLLYNL S0- LP T W QYNWDVVQYASIVIAKS RAS S QF ENLY LSP NP L VASIVIAKS RAS S QF ENLY LSP 9 D NEIS YKIQS MVDK KAG F ELAVLYNTD AEQDTF L MVDK KAG F LAVLYNTD AEQ 6 G N VKVTQF VHQ D AL RA EMVRQIIRLLC G ES HEKVGHLM E VRRA QIIRLLC G ES HEK 47 NLYAW1 P QGD W HP A R DD K F EIQTITGEA DD K F EIQ RS AF S V 0 GRF DQF K RV G LDTEA ADNMDAS P S VR R F DQF K RV G DTEA ADNMD L HDEGIR N K VLQ LQVRKEIN K LVLQ LQVR2A:.LDF KRA P P HF EYP S R WR AP S H E P S R WR A TET LRADP HG HT HP RQRDIY V GY TNF HTY TQLKA P CVTKHP RQRDIY V GY TQLKA P C P QV P H R G KP P H T Y T EF S R L A A G AR F R o P R K G T L T Y T E S R L A A G A P R KNtekc8 9 0 1o 75 75 85 85 1Dvy9enrUF T - i LyG - ZR - 1 ZR 8ottNI_sp C 2 y _RysTysT 0 T p_4LLy 7 - p_ y 47L- 608 A C L R G 3 - G 1 M G 1 M 21L L NR HV S K WR VD VR KIW LK QV DT P E WA KQ GY RK PNIQN NE FIV LA KQ MIL GRITG E MIIL A GD NK AE RV EL VC LA GD NE S P EP GS HE RA VS S A AF V V HIRKIS TG GIA QK DA CE F E NP RTIF A AEDA N EDP Q P NELF GYKDLDKGADP E GVYKALVIS VRLQAP S G M NKLK EQEH QQRNIYWF Q KLNDARALLP C L F L P LHRP HAAC YRK AF P KS V EQIDF LGAHIN S F LPIP W P NV YQD NSIV AVL F AS RLIH VV RTS DLG RRKAQF NNS NEQ L AAHNIP QG NKIEDDME Q L F KYY ES GQ QL TK NQHS MLV ARLDL K N MAS QRDIKHT 5 TKR 4 RQQN LMS NAL HMM L AS DP P YRM KK TAIMF L F VDS EK KAAMS TNLYIA LKLS 0 GF NP L KG KNNNS SS RNE DDAKL TK EKT LLMP KEIW S C KS L F N Y ASIVIA S S Q L S0- DTV L REEIVQ LV GYAIRP N EGAPGICIRS P G K RA REE VDKLAKAGEN NTDL EP 96 VF T GHRK VN DLDCTK 4 RDAGS NIDA VWAQ I EP RT M R LMF ERAVIILY RLLCAGQ K 7TITGRR LSF NNCD MRKLLKIH KLKLWR AAKHL AT EAVR VRQDDGKESF H EEIQ 1 AS P REK NAN LN V DS W RAQ KKKL TF EARQ TL R S V L* S T F DQF K RV LDTEA ADNMD 0 K2P SINNK V S AADC:.VTIAF KNES Y QN KQ GANRMR VDMR LRRHNEKP S VLQ L R WRQVR A HEEH TG LN E L A PGF HTYRDY V GY TK AR KS AS QAVKNNRV G T L Q AE S M T L D D A QL S C V K V G LIHP RQFITQLKARP C o L N K L A F E T Y T E S R L A A G A P R KNtekc2 3o 85 85 1DvyeF - 91nr- n o L ARysZR _T 86ttE_T L B93 - py 47L- 08 A u G 1 M 21t,,.%rDo d O P O P O A P G NR g HV.0 e 7 (tRT E F K K L S KsWRaKR F P WQ G A HEVHLILEK RP CVIY CS NN VELM P G VDMeleltGV S VA F T RQAN LR E A P QL DRIL L K NS VR KIWbaaRS TDR D R g LLR RC RWRS TTIA G TSKIERF S T AVRF S DRTIWD ALR VS LKTQV oniS T RF L VN P E E G NL S A tvaERRQF T VN VRL KWAKL AM T AKDA* D GSLIDT* F S R P EV ghS F AYEG HS DTYIF R S S A KQTEANKIAniRHVS VL RAA L L VGV E W YecGIKQP RHGH KHR VVG KQ GYY RdronA e DP AEARN TS TQ DDEP HGK T Y L NT GN D VGLRAP Y RK L DSP PNIQN NE FIV LA KQ MIL GRITG E MIIL A GD NK AE RV EL VC LA GD NE S P EP GS HE RA VS S A AF V V HIRKIS TG GIA QK DA CE F EPN G P N V S RKV Q RTIVpeel99 n LV R EK AP LWR LEP E KTP DTT P LLL N F AT pbAEDa rotGLGCAA A KKGF L GTP CS TTLTD* F DELIEylT u RS * G F RQWN G H DP S GN opfo G R o,a- GLRLDAF ADF AP EP LQGTT GS LV T HVGP KTS AF GMLF S NL DF F LA QLVe% n T htR 8 o S AAP P Q TL CRGN P N L T VKCQAA ADTPF T 9 n QLLLT D GWL S LGNQTNDL DP TGS E P SS L 5 TKR 40 GF R,stL’ ,%rq HLK ofesRAAYP NGLRS S T ES AVY VYDAACL L ELS VDL CLTPQIKRNVYLE YLQ0- NP L DTV F Lne3d 79, s_ D e A EYTRAT RPIIQH P EA DHTGREP CGP T LP D L A P ED Q T CS 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DAQLT QD GWL TL P Q P MIIK VPL TAF R LYL VA KIS A LTN RS DS LT ES GHMIN L NF K L TKIK G KG S AL VL AELVQVAS YQF RRR RVCV E TF LK DRP 54 CLTPQIKRSS P L V S DDQP HNINIR SSIVQF RIKNCLD H KAK R DS GLAA GV A ETV RNY 0 H0A- GR P T TP EH AVQVYKS Y K K N V F NWKA N EDHT AG F P AT LP L DVDKVENLGLLDFDIV 9 TECS S A P NL SS QL S VDLQKL S P QGAALS GS NF DYIQIDCS LKIYVAGVKIP CRVAL 6 RLK4 TL W VY N LLNEVLK P EA F A KCCAA F G Q E 7 S WR G R KDF DDKIQLF AR AF RTIANIDRF1 VV KKQ NRF GC LQP F P WGL F F VVWNT FIK S P 0 R AWT LH P W VMGNELARGKTDCF D A HGLS VNY2PDICVVH D T VS DRDIG EL D AG ES LLRHF RYVD G RKEKR RYCQEVQL EM KCQNR:.A V A A E V R H Y W K QN S L F KLIV EN P DF S CH VK F GA F Y D Q K N R R W A L E TT S K KNIN K oNte0kc9 1 2 3 4 5 95 95 95 95o 1Dy- - -iv9en- - - S - -r1vaysOysR - S y - G 1 s OysC 86ottVF GR p_R p GR p_R p_ T y 7 T y _ y 9 y 2 R 0 S _ 1 L 9 9 T 3 T 0 T 8 A G 1 L G 5 L G 2 L G 1 L 21D Q T W K F L T N K T L L R N LP M AIKS Y G K VF K R* YG YW NN AT LV GS LC F L S R RN VG DN H QWINC KR PLILP C YYIS T KK VQ AF DIDP KY SP A NLIVPS D T D F AGVIF V T T A Q KINTDS MTDP ML N E NIIH S AP P CAK LTLLAA E QVGT P KAKT S YMTVDTRR S RLDIHVD P PIP A LGQIANLGQP ALF S L S TMRRK TLTILIGIGKL A S HK NF YLL GTINP DD LATTNY AVLS HN AK A HLNH DLID R F GCICP CQADRC S M 5 AF M LFIVEHKGQK N TA4 K EAKP VL* CKQILP QDLP P D Y QA MDIN KGLIRIKTKKDEL LLDG DLG 0 AQ0-IIKKY LP E ELENVE R QR E E A P F Y VVVQQTDW L W L QM K RLRC P DE CLQA P VS G L LEWDAEF L LQ S NEQGR GCY TAQY P S KIITQVAKGS AQD P V RTA L S CMD 9 HS GKYEA6 GDF S QQHNTRH L YTLLLIQIP TVS F GGEF GVS L VHIQP G TNVA RDSITLF HD S GF RRS VL Q VTVYRTVIEYA NWF S DS KLN DAYHIQPILRLEF RV 4 LFIY S YE KS GNL P REREIP VHG LVAS P L TG T S QV MPIHVLRIIPAITV GLTV 71 A0 NT GAF QQYDL S DTVEHS F TP EDP P GKP QL AINAV EEWKHK DF KS KYPNIRP2HLLRS S P VD HLP DK NP Q F A HVV R Y S VQ GIE C K L T GIL G P K P YS GVCTL DP G LF AKENV S G Q LK P G RT P Q T A L V L R R A G:.E G K L C M N H V S N D Y D D G GoNte5 6 7 8 9kc95 95 95 95 95o 1Dy -e- v - - ATa i91nrys- - RysAMIL_ -1 R - B mysS 86o ptty GRp TR T T y _T M V R p_R R AT y 6 T 0 G_ 1 L G1 A T _ 3 8 A 1 L F _ R E 6 L G 1 L 21I L KR S Q NG HN YV AK KF EL RT WG EE ED LN EQ S L LTQIA MG RH RS YS DS GNIAV VK DF LP DG ME NW WKS RR KIL AK G WH HG AF KL F K E LV ERS VP N LF L HL CV TK KD GG YP VT LF QE YK P KHY SKIVNDGATE H LVS NHKTP HLKGS G DL KM MTNTDATSVIVR V E AS AS N APTIRPIEP S LS AEHG L GAGWIDEKTKG NL G P MNKG LS LVTKR MR GIKDIKF L GDNQNP LGQEAF DEDY GDIVLV A DELQ F C ACKIQ GTAK VA YWP YRIE GVIMTS NKTMN CEAS GVCVP AR V E EKS VKNP HL TT TD EL QNLL F TKAVF 5 P D 4 THE L NVF TD LS QHG R 0 LVQP RRKT AGVS LKKEG YLITA NVKLD EVKR LLVKIK E GDS F RDVCWLITT GGLR G P RVRVE P QVV T YGDS S G N L TN MKVV RTNWAK0- YW D F96 ARKLIVV ANF E Q QHVARHIP RP A TSVIF EP LEP EKGF LK HPLTF GAN L KNMYEA LY TLK TKS F V S LP V A N VS KA NWLY EK KHK NY NKNKIKKGLY S P AG 4 T RVP F P E S V N G VKLKAKLDELGPIMGRGF P EK S P F AP LG KF STA I TP NDKN 71 YRI0 AELIF P YS YP P F QDP S A DGAAL V T G D KQT RDLKM L C THVEVITD LDAFIEKIKL CF KD F HP P A P HT RER VAVTLIAL L QWEASEIS NLC K N AP Y KS RL EKS2:.W Y KM P P K E Y DS Q A P R G H ES M L S S AW D N K R W S H M H M S H G W D T T A * K S G L G E W K L D AoNte0 1 2 3kc06 06 06 06o 1Dvy-ie- nr- - CnryM n 91 s A - y C - y Z - A 8 p DRs_Rs_ L D 6otty _ p 3 T y C2 T p L - y 8 R 9 T E_R 1 T 08 A G 1 L G 6 G 1 L B 2 L 21NY F N QR F M EL Q QNIKG KIG IIH L MT EN AK EH KA LD ER KIIAL TT LFSIKN P G NK S D NL TIIRP TH KK MV RE LF F A RIA VKS YN AIQ VL RR TG LG KV HIR CLIS G F KNIQD L MF LP EN YIL AGIIATQ GIQ D KEF NH TLLL D LK KK A Q LTKL S TA P L DKS KLHP NRY VT*PIQS RN L GM VKT AEL LNIGHNF D MAKP GAGHIVIAH AGWN K TSIIIHIPSEIELF Y* LF KEG T* D E EK A KDN LRDGF E QQARAQPGIF K VD VEIG I N KAAAEQL TD L EF Q LHRRLWIDGQPEILAF F YN P HW CAL H RYV W P HVRYGW 5 VELKP P DVCAV LMLLKS* E YEE G L VD D ALT L LHVDITTYIKK S ELDILIR 4 LK TILKC F LAL*IS TGILK VNRVV K S VKYP S AC E CLDLGT LLF WL CNLQIEP 00- TGGIA 9 NTVMHP LS RTSIYQ RP LLQLNF KE * AK D TS L RKEP S LLGP G E QN S NGRQP GRKA TP NVSLDQ QERIM EQE 6LIR CW** TRM V VGYKNKNP VWWL LQNAR R4 LLW YVQ7IGIWIGK L LRLMECR* S * K LP RTVSIYF K LEF TVYF GS TT YK P DGFICVEGWQLAGN P S AS P WK P TG S YKF 1 EKIR AF S AMT YV A KG E S TVKWY GQ LM RVEF AP LN* E*S D*LIL* RKNWP LM C AS A L ARWNP EIM G F YCNWPIT 02EEQAIKH MK E P S AGF P ES PMG W VAM M K V Y QGH K VTLY T MAETKIRT P C V V L Q L R L L M D L K E D T A TKVQAMAQGYLTL:.A L D V P R F K A S H L T P D F KoNte4kc0 5 6 06o 1D- vye- M -i91nrysZ o p_ - M 86tty 4 R V R T R AT 0 G71 _ 8 A L E 1 L 21D Q L V Y N D K G KS Q NP L H N V K KIQ S W H A W WF R K QP G E L Q V LSP G L K* AS VP VTP TH YP QP G EQ H WD RV AL KP P KF KT L QS TIIRAR EGTIQH TQPE P C ED LG APIS S P H K EHGAADMADQAGVF EDS TNEIWHGIS NNLWF TWQP S LEILIN P S S NLAAF GDNAKADAS TKS S DAAFIAS RHLVDP KHNE P LSLIVDELG YLYT GS QE GVVLV Y CVP AP S RAVGV ALDYKAA EP AD AES ALP S Q KLPIGV DP P QICD5IEILP GVF L S ATS TTEHEK NP P QRR TE Y RV AR LLKK DEL RAKKTTYG 4 AHP GRK 0 RVG LRAGEA T QLLKS HNVRCP R AMITNS LK TDKFS LAS HTLVGGH Y0- G YAARHIQVP P RVMK EKS VNS RL P DRRDIVRNWENP AMVGIGGGF KRVH VTT S D VKMN D S QGE KA A Y KG FTIEID S AQHP S KD EP TC QVQF ATS 9 MDF S LP V QA N VVIKP RRP AIAQ W E ADLGIIT G MF AYAAVMS YVTVDLS KT 64 VF EGPLIMGDHR F P LGIVD YKALF QKS GDDVGGVKTILDAV TAAP DYH 7 Q10 DQF G DGAAL F K KQT S P QM RLLGYS RF NKKP KN EVTKTVLIF VMCHLH P Q2ADAVA VYP F S VTLIVQDLILP AKVIF YATL AVTF CNQF RP RDVNYGTI:.VKA P R WG EH S H M H Q Q V D L AL P Q S GEEVERVRYS NGL V F L T K V E Q Y G QTIT L ASIGAS S HQ S ERS S Q LLID oNte60 70 8kc6 6 06o ir1D2 vye- C L -i91nrysC U -o p_ FysG 8tty CR R T p CR 6 2 TNIL y _0 T 08 A G 6L- C _ G 3 L 21S LG GQKIP Q VG KQINQ VG KIQ LT VQ QS DQ T GE QP QV F E NF PIN P NS R NM KV DEP HD RIH KY NL QK TL QN HS A WN EIM N EMS KG AIH KL DK F N VD RS MCNR RDWE E E S QS GKAKADRSQS GKAKADRSQS GKAKADR ALTTIL DKP DDF E EATKRP E AIDDF E F KEERIAP EATKRP E AIDDF REP E A F KEERIAP ATKK ERIA F K EYDS VS F L DGTF P E R ACDVS F L P R ACDVES F LF REACD ELKF RAAGE TF EKRAAGE TF P EKRAAGE RITF S DEF P QVMLF EF ELP F QVMLF EF ELP F QV LF VDS GVS H GKDKS S GVS H GK KS S GVS H GKMKS YNV AAAQYEQTEQAAAQYEQD TEQAAAQYEQDEQ AP EWE TKQVP LAF DKEKQVP L F DKEKQVP L F TDK KGQEIEVS RLR LLIS T EVS L A R LLIS T E S L ALLIS AV G Q D LKV KKDIA R G D LK KKDIA VR R K GKKDIA DD KVPYIM ELKTNIGH M EV LKTNIGHDMLEVKTNIGH I QE G REKAKDNL GE G EKAKDNL GE GKA L K NL GE ARVRRAWID LRP DF A AWID LRP DF AEAWID D LRDF A EL EGQEILF R EL EGQEILF RL EGQPEILF 5 MYQG DY E G L 4 S P VNVVVDKA YLT L DY E G L P S AC VVVDKA YLT L EDY E G L P S AC VVVDKA T L YLP S AC 0 EGQ0- LD KR GF AKS VKD S LKEP S EGGRKS VKDS EGGRKS VKDS EGG LLP E AS LKEP LLP E AS LKEP LP E 9 P 6 DA RT KDIS VRVG V 4 L QGRTIYKY EKNKNT VYF S VRVG VIYKY NKNT EKVYF S VRVG L VIYKY NKN EKVYF 7 ADGR S F LF TP DGFRTS F LF TP DFRTS F LF TF1 VY L VKA KG ECIVKA G KG ECIVKA P DG KG ECILQF R NWP LMAS AR NWP LMAS AR NWP LMAS A 02DKNKAGF P E TS MAP ETKMIAGF P E TS MAP ETKMIAGF P E TS P MAETKMI:.Y S Q K M D L K E D T A A L M D L K E D T A A L M D L K E D T A A L oNte9 0 2kc06 16 16o 1D- - - vy9e- M - M - M 1nrysZyZyZ 8 p_s_s_ 6otty 4 R p T y 4 R p R T y 4 T 0 G71 L 7 7 8 A G 1 L G 1 L 21,% _3sta5 h 7rt, eniv a;i m L L OL L L ,.%rDo d O P O P R P O P O P O P g.0 e 7 (tsNaGGLP S AA R GE QS M QAA AF F T EIAL LL SEL I LM Y S AY S GIE H AKF DMNIelelbtQRS V TRRRP EV YP A R AM LGE P S LR HEAWAITQ VRF WLIL R VYIL E aaTR S RRN LLP AE P P RER LK P R S D P T KES A KRID EDNA EC T g P D LE Y L otg nidroccaecneu qesdicao nimanasesirp mocrehtrufrevir,.d e.di,tpepbyl aTrooteus_ AE S ES W F V A MC LS ELVDS I F KAGHE RVSDIS L LVQ K N GTGEYQIL AAKINAV RA of ,A GS G A T TS GVGDRQQCA P LDQK V p eo%a- n A QLG GGS P A ARLP VALEVAP EP SGIGVEAS RF C QE P VDIS ETKNCT t R 8 o _3 VCVALAHP P VDL L K A E TKIh,T 9 L,nreARVEIS ALL ATLRV HGRTNKQ Y TDA v E DHGEIP P P PIR ER KV DKIE F KF LREL GEK LGDGP YMQKRCE 540st ’ ri3%7of rHP F A S GLG R VH R HDRGL HQ LNR LEP S Q TT D G D G K V H Q0-ned 9sE W R S A S L S G A L L E K S T K L Q A K L K A F V K964min,e7 da%cn Q 5 7 8 0 3 1 o 0 b R 6 T 9eE O1 1 1 2 2 u SDIN 6 6 6 6 62:.meL,’%qeoe5Ne59s3R R R Ttm h,eot%reT R L- R T T L c TL L- -ikcsonIots0 v 9Dd,irAL- -o S G M D P O Cyn D:_9 B C _ _ _ 7 _2 1venr ]o % 3 p 5 3 9 0 9 s 8N re3-1y- A1-1- 1 sys1y y8te ,elv Vs s6ot50rr% bi0 arpy py p p R y y 0 D G 8 A0[oc8 T G E G G 21P A K N L E E TP L L A V D LP LS M E K GF V M Y YPSF G TS Q TSPS M R* F K AQ MV LID S K P V LIN EQ DK WA QL TE QQ EIIKK QV CK YHAVWP LVDGP HVR RVR RL F L TL EVMS DE QREDIVTNEES T R RVR REVMS DE QREDILE TGTEGL RF P DS LMP P F AS GDA Y ERVHL G Y A DTRF RVPIP P A YHLY S LRHS AGS GD ERVGA D S KGL P E QVNVWSFIDE QGGREMIWEV EAHN CCEQF VKFPIETTS Q TGL RREMIWEV EAHN CCEQF VK 54 AYF F F F GLLGCRE LAGDHKVV S TR AEC ARS AIRE LARS EA AH MD VM TDAS AS TF NDS RQAP A VT CRE ARS AIA EA H MD GDRTRL DAS ARS VM TTF N 00- T D W M DL T G CP T T A L N QP P D W H C VT G P Q H L D RCP L A K F S V A H C V P Q H L D R P P T 964 4 5 0 5 7 2 2 3 3 1 6 6 6 6 02:.R Ro T TNRLteR T T -kcL-L-irL-irC C R A C C o T _ _ G _ C 1Dy_e11 2 C2 v -1-6-6- 91nrysy y y8 pspsps6otty y y py 08 A G G G G 21KS S Q F P RH DY TIA T VT LL VY HH QR NVGG RV R YEN H oneLS GGPICKQDILV LF RY T MG S LVTAccu LF S T GGS RP VS VIIW AL RN V S L q S M GA RLKLTADIF VED K D EKLWYa esAERSRIELQ LT E TFF R KC P P KVSRGEeP G HS P F V GSITQc aYVWVF P AGP L T P ATK A P MVDD MIP Vne rS T CQREPS GP L ATDGDEF QAAYIA VNWL u o GEDP LTRAS R F L API IV LF T F S DEIG K TMP KDqe )B S TV TL WV F P L KAQ LKRDLY ADTTR R LRTs4 TP GGAS H ES P V LAEP A DAHKV MAVYTW EDQYSId TR AAi ET RYGMA S TV S QNATP F A H EcF N ARGP F QR ETGIelTY QP R LLK VQTKDV L A TK DV VAa ba sT N HALS RQG P P Q GQ F P NQS AY GTYIP V o n n LNiT oA RF ARP GETAWP QC EGY AAS E ES EA S RT HKF KV R m niso P F LLT ETP QS Q L S DS S RDLT*P P D L GT AL AV P F Y LR KP LA DG KY QV NY KV VW LN TD GL RF TA AN AA CV S TVS VTRAA R CALR L AAVQLG NTTP TD RS AS EYKFpeelD AS TVIAHLL pb9 oea 9 nsTRErot_ AIS ARRTKA P RKAPS LKVILS LT FIP QY S RRP E KVSLIRTR R EES T QQELP N TylT o u A S KS DD LGT RF F Q VTNRPIRF ERES S of ,aS LR A - _4 S S T TWA P EV P AF T TRF V HAP H p P DGP P R S HS G MKo% F APILEQVVenreGTR R TP P AATTRD ETTS Q V TGL R 8 o v LAS G NQP ARAAP RMGhtT 9 nirSP RMIGAKQP W RG5 S QAP T S TVCTE4 DR V LS VF,L, rF D D G W E A G V R RF P W P D A 0 S TGDRTR TEA K0- A L N QP P D WK M P G E E L Kstn’e3% d 7o9fsO96mina,ecQN6 74 6 7 3 d %6neE SDI46 46 1 6 o 0 b R T 9 u2:.meL,’qeoe5 %5sNtmeh 9,4ReokcR Ts t ro%eR T v TL-o Ln_I ts09irL- o d,D D P C 1D2 n %:B_ _ vyeL U]op 5O r 1- 3 9 A 1nrF 4se8,el evys1 86ottNI50rr% birpy V R 08 A C0[oc0 a 8 T D G E 21t ttcg a cttttctgaacgta L, ,Ot%irmo O % g gtag ataaggttP,.g 0 D d Pta0aaa.7ttcttaa athct7ttgttactggtg ga ttgtGGeRE( saA LF R,.AP R gstP KP elNS VP A.aatagtt ceelt g taccctttgt agctgttLLel tS PaV(tgtttgctttttHHagagtgtcata EKbaaES W T g KLAK VQQ actag gttctg DRelgg gtg gga cat aVV TIFP ontiv LP S RS Lni aRLIbavgctt atattccagctgctttaGT gah KKELTah gccttggacgtAR FnieGAP R oe ttctaggattagtCW KDdr cLER oneYYLS Etc tCMML g nineacgttctttg ttt atgatg gtttt cg g VD P MD S E RG VL AE EA LQ Y KDIRV MMIR VPsntctcGCRaETV oba sT n S LA GP AS LSdibaos cg gttcgagactcagt ccaES KniTKDM nosG T R AAcTNRPaTn otpttat aagt cgtcatatatg ctAKP m EP Qa io Fd psK TLLRPcF DF Pieidsngatctgtgct agc at caS MQIna etan P KAKRL TLGlc etaartttaaaatc gctaattg g KCP Gsa DTTescidrtRA PFITWL utV AVANEn ciorctg atccgtcctatccc 65 Vadaattaatcaa3 YRirnorCVE ntettgta tttgc fQF Y piS VL gteMTT S RTK GD y Eb igr ctatgtg cg ctggtttcao4 AEQ m VF G o nirrDRF TDLDSdenirR Ttttag agata agttc tttta41 LF VSIcr ia .R o T AGVEIV F P AS S d oia .oL gattgaatgcgtaaaK Vtt eS G DP TS RH VP LG LG RC RA VT GT LK AA KL T ADEyoyo KaRAD o - _aaED pfo,u %a- A_ L TAA GF WC n 5 r AS VKL o D pfo,n Tcg% o Naa agcaaac agttgct c cacgtLKPeR 8eT AeR 8 n_ta tta g t gtGNLhtT 9 5 M Q W,on v LA irAVLMR S ThtT 9, rne cgtaa c ctacgcc ctga4,stL’%rF F D L EK S P V L,stL’o %fmcttttaga cctag ca a00-ne3d 79ofsne3d 79ecelEt ttgt at tcca_attg gct tga at9 4 4mn,eOmn,nellgtt aagcttg6 9ia%cQN8ia% u ua cttgat gt7 6 d 1 o 0 b R 6 T 9neE SDI7 d 6 o R 6 Fat9qe_ctgtgt tcattcgtg g at2:.meL,u b T ’qemeL,’s rrevgtgt accaag ictttgacgtgaco Re5 %5N9sRe5 %5evrDGagtga aagat attcctT me ,5T me9,ireL- o hkcSs t%reo h vL-s t%do O_nIot09irS On ot09llu Q E O62D7sd,D _I7sd,Fy9 n:SDIN 5 1ve1- o %5:9 n P1- o %5Q- y 91nrys ]po p 5tty 5se8,elrevy0rr% bais ]p r p 6 y 5se8,elrevy0rr% baisL 8 r p A y _R 7 T 60 L 8 A G0[oc08 T D G0[oc08 T D G 3 - 21atttc t atattg ttcgag a gtgcc ctggagtt acaagtt g a actaat c g cacg ggtat ctt tttaactcgtctaaaatgctggtttctt g gaaa gactt cagctcg gcga at agaaacgtttg ga c agtg attgtttagtcatttgttacaacatgctacttatg aagaattttccacacttctatagtatcattgtgatttctattccgacaactcaag ctatactcg g atttccagtg taacgtttttcatagcag gttttatagctactttat gtattgtgtgtttctgtc g a g gtatacg g g gtg t g cctgtg tactctcgctctcc g agatattacaacactcatacaaatgcacttaac ac a a atata ggg ata agagt cgcccaaaa agaaa agcg ggcaaacttacg gtgtgtaac atgcaa tta caatacg g g a g gaagaac acat gaaatac tgcataaccgttttgt caagcagag g gctatttag gcgcacgtta t aggtcga acataacg gt t ctgcctc a t ac gaggt cgtaa a ccttag g g g gcaaa aa gtgagc aaacgtaggcagt acg gagaaaaat atagag tag a g g cttattagtactcgactttaatg gggttat tac ccc gaacgaccaa cctttaa5 g g a 4atattcgtatctttttgtgtagctgcggcgaccccgtgagtta aagt agtc cagagaa catcgaatgct aaagcggagtcgtgctc ggtg gg0tt-ccg g ggtgcacgaaaggaaggaactacttgttaacttttg0cta attgtccag ttgc ga cag gc ttttatattccat aga caag acta gcaaaagacaatct9gctcttccgga ct atg tactagacaaaatatgtacttc gt cgt aa gat actt taactgagcgtcgcaccccactcgatacca6t tt ctaga actcctctctaaagagacaaa cccc attcctcccacagaggatc ttaat agtatagg g aaga aggt agt ctgtgacaagaac4agtaat gtttttctct aaaagacccagttc ttttcact gagagtcta ag acaaattcga aataacgaaagaacgatcagcctct aaatctaaa71a0c agtcgt ccgtgtgag tg acgaaacctaaaa ag g gttt accat aa cg catttgt attcacaggt gatactgagaccactt ga acccg acttgg2 tg atctta tgatcaaccttatgaatag gttg actat taatatccagttagaagatacaggaaaagt attttattcgag g aagctgtagcagt:c.taoatttg ttcttccaaggaaaa cg g g ggattg gcatcttgagaccccaaccgat agttg g gaaaa ctggagcgat atttgcgtaacctggaacgatc aggaaactttactg gaag tatgtgtg gcc aagataag gttga actatcagcggacag gcacaNtekco 1Dvy9e1nr86ott08 A 21agaaatttctt t ag aaacctctcac tgttttta ataaag g gcccaat at ccct t g t tattagacaatca c gtag t gatct gatgaacttcgttattcactcca c gattacttt gattattccctccgctcatccaatttttgatag atactctcctcccgtag ggtacgttg atg tctag g aaatgctggtt agaagatcttggaaaaag g tag aacctccttttactgtcaaaagatcatgaccccgctatcgttctagagctatgaatacg gatcgagtg g g g tcacgttacagta g a g attcg taacaaccgtctattatg aagagtacctt ccagctaaacgttag g gta tc a tt ccgaa agt a a attgc agctcaaatgttt ctt aggaga ct ct cttc act aacttctg gaag gctctgtttaccc agca ct cacagtaccttccagtcctag gtcaagtctgaactcatacaataca aag actctacattag gag cgcgaaa gcatg gcga caga tg ggagaatttgctttcg attg g agagaccgt ttaactaaccag ga a att5 gactg aatcttt agacccaattgttttcggagccccaacaagtattacgtttagcgtgt ctcc aa ggatttt cta cttg atcataacca4tagtgattaaaacg tacttt gatcgag g cg tcgtaccgca acaa tctgccgaccttgttta tcgca a ag g gattagaggagt gatt aagctcta0t0cacacctgaaaag a- gctgtctat ca g tttat t agtaacgaaaat cacttgagcacccaaccctcttgaac caatgaaaatga ag gacc ac gcg g9gatt agaaaagcgg attattttt ag gtcatcagaaaaata ct aaagagacgtc actttaatcctg gggagggttatacgtacgatccttc6tcgtgagtgacaactata g tctataagatcaactaca ggtctgt aactaggcgcaaatatttcgattatgtaga ctt agcggaga tgatc4acg7at aattaaattgccaacccctagtt ctgtggcat cccccgttagctggacaacaact cctttttaagcagttcttgaaaacg gcg gaaacta10gaat ccgaatagtttgtctacccc ta g a gtcgaac a acc caatgtaccgctaacc ccattgg gcttttgagtgacct aagcttttg aact ac2 g ca cg ggatt cgcatcgctcaaatat agcttacgcg g gttcgaccttgccac cagtt aa ttactaatatactgtgtc attaagtcttt tgca:c.tgag ocg gaactg ggtg gaag gatgtcaccaatgagacctcgggtctcaccccgagactta ag g g g gcgta ccagaaccagacacgt agcc cttgatatttgtcatgttccc agtgattgggtgatgaagcgtatttgaaattcagt ac gctg gcacgcaNtekco 1Dvy9e1nr86ott08 A 21c cta ttat cttatggtt t gttg t t gta tccttctttg a ctgac g a t accc tatgtt ctagatcctcgtgtaaatgagcac g gtac atgaactagttataaacgt ccg a ga gtctt cact ctga t aa a tgatgacttttctttatgatggtttttcttcggtctttgattttcgaatgtataatttcctcagatcctctacattattagcgactcccttaatagtag gttcttagtagcgtatcactttatct gtag gcattctaatacctaactg ccaca g atccttttaT ttttacttaagaccatgcctggtgcataGaacttgctttagaaaatgcaaacgagctattgtaaca cctaattttcac att gt ctgtaccggt aaagt tttaagtttttgact cgaaacgaa acaaccg gt cgtctaatctagga cgtcgaacatt aattc g acactg aca attcagtcctcg aacaccacacgtactttcggcgttttttgatat ag t gtt at gctacgtgcgcgttacg gacac ca gc ctttaa aa aga gaagcccc ctagtccatag attagt gaag ctaggtt atctagagttttcat ccac taaacgcttagagtc c atcttactgta acgtt ctgaagccacggtctgaatcctctat gagcgg gcagtct5g4cttgtag gggaccgaa acagtccgtc cgtcctaacc a ccg gtgca c agaggtg gttaccccatcttaa ctcctca cgtccag gtaacgttaatatt0acgagagtc0tgata tctgc t-tatagt gttta att acttccagg ga ag tcctaaagcatgccctt caacaagaaa caataacta cttg cacacgttcaaggaagagtctttgtt agttattttgtctttgcaaacctt ttattaaaca ggatttccg g gcagaagacgt ctttta g attt aa accagtt aa9g6ca4tactgttccg gaat ct gtgggttgatcaaga ctt agagctgcaaagatagtattcaagtatgg gactttattttat cttccccgt atcc actgt7 gatccttagagttctttgt ttatttgttcagtttctacg gatttaaagctag acgtccagagaat cttg gtgc cg gta agta aacgctcgataa1tag0atac2attttatatgtg gtgt t cg g gacctgtgtaa ccgtgtcagtccgagcaggtttatatag gc c cacgtactag ccatctgcctgac c ctatattgtagtaaataga cgtggccg ctcaag gttca agcgctct agta:tg.cct gt t c actttacg g gt aagacctgcct accggatctatcgttgattcc gtgtaaatcctacctaacg aGgtataaagatccccttt ca gagtttaca c aacagtgcaacagag gtgtg tcgt ct gtctcttcaa tcc aoaat agc agt c c ag gattt a a attttg gct aga a aggt a ag gact agt aatctNtekc7o 25 1Dvy9e-nrysAR 18o p_Ttty BL- 6 7 y 08 A G 3 L 21acatac a a gctgtcggattgt caa a g a caatccagaattgg gcctaacaacg c acttttgcc catg acc g aa ctt tctataa a c g cttttaat agaacgttctgc attgat cacgccg tt t aga a tgc c aggt cgagaaaatgacgcattg cttaaccagt ctcttt aaacagttctagaaaaagggaatgaataccatag g tttaacatgtccgtcaaactgatataaccacagtagtcaaaacttttat ctcttaag ggtatcgataacttccg a g ttaacgttctcgattgtctagtgcaaatactaatgataccaacaaactataagttctggt atctag gtgaatagagagat cttcacgttcggagttttcg gtcaaagtaacgttgagag ctacg aacaagacgagggtcgtcgaacaagcg gtag gaa cggaaagtgc gtgtcatac a gca tc acgtcctg gcgtagatggaaaattatt ggtgag g t ggtatgttact ac tgat agtaaaaagcta atctc ac cttcagttt attttgatctaacttcaa cttcaact gaac aa 5gaatccgg gttc attgttggat4aatgca acgcgacattgatcctacttgact tgcgt gtacgtcat aaccccagctcttcgagagagtgtacgca ctgggc cggaac agagcagacg acgttta acccccgc attatttgacactctctctgttattgttgg gttacagtat ctc agag gt tagagag 0agtaagtg gg0-ccta aactcaaca ag gtt tc cgctaa agataa cctccattgctg gctt a cgtctg gctcaagtcaactcgc tgaggagaccgtt a9tt acgagttgtcaagag gca attt agat aa gt ct aactatttaataacatcttctg cttgtt ct gagcccggtgg gcta cg gtag cacctgagtttaaacata ag ga agcagag gagcttattcttgttaaaa cat atgttatctc cttaagatcgtt ctt aatcacgacc aggtcg gagcac64 g 7ttccataag g agaatacggtgtgcaaatgcctacgctg taagtgt tcatttccttccgttttc ccaccaacctctcctaggt catcct tcaca1a0cttatct2tcaat acgtacatgtcttgataa attg cctgagtgcagagc atcctac cgaccctatcatccccaa aaaaactttaaa acga gcgtcg gtc agtttgagtggcaagatggatatgaggcccag aagt cact agtacgcca ccactcattggtgtg ctt cacgta caaga ccgtgagag:.gaccttttgttgtcataa aaagtcagatcaag g actggagtgaatctgt tgcaac acctacttcat ctcgataacggagtagag ggcttgctoccttccctacgttagtggacccaatctgacg gaaggaaacccagtccccaaaggactg gattccaacgccNtekco 1Dvy9e1nr86ott08 A 21ttgaaatcttaa ctcgttaatac gtagtt t cttctacact aatg gttttgagtatcttctttctc c g g c gcac agc ccaagt gtaggcgac ccacg acaagttcgat t a cacg ggc ct c a ctcactctttccctccatacaat agaaaggttctactctgtgtttatttgctttacgtttgtacctgtttcgtttg ttttatatttacgtcgtt g tttctaaccg cttat ctattaattctaagtatcattcttcgatcttctttacgtctattccgatcttgagtg attag ggtacgttcata g a g ctg t g caaattg c g taacactcatgg ccgaacg tagg gtg agtgttg g aaa agtt gtga gtttg gtttgt a gtcgctcacaatctatcgtcatc ctccttcgaaacgattcaggacttgtgtcttggcgctcaccgtcgttat aag gt cctat aggctttcactttt aacgttaagcccgctctcagttatgcc ag g ggacagctgta tg g cccgcgg gcaa ttc attg ttgagca agt at atgtatctagctga tc cg ct a cg gacacggt acgc agaaacttaa aataaag atttga cggtcaaa catgtt ctatgcctgt agc ta ataacctgcggcgg gg ggacg ggc gcct acca agcc5cagt4gata tatattgaga ca g atttt ga ttagga aa cgtaaa atcaagca tgct attttccg gac gtt tcgcg ca acgc caaa cgtccttaacctt0aaca0- gtaaaactttttcctg t gaa ag gcgctat9cg gtgg aa tat tttaacacc gtatctaatcctcatca gt tctaactcccaagcaggcaac ca gatg g gcatcgttcgtgatattgttgtttt cttgtcttagagcgattttgaa ctt cattcatttagcctg acg catttcgat cgaatttagcg gga6ctctatgttccagaa c4aaga cttaccgagtac ccataacc ctcatgtctg gtatgctctata caaaagag g acg caac gtttaaca cac gg gg gagactaaaaaatactcagctttggaaatcgag gttgtaagaaattgtaggtatct tcgaacg acaccccggcccggc ccgccg ctgt ctcaa71a0 gagcaagtcgt caagttcccgtacttctgac cacccg aat aggatata gtttctaatttaatcaaaaacggctacaagatgctctttatgga ag2 a acaac:gat c aggaga. aaattctttgtctactataaacggcctacgag g gt a attgtgtattag gcgtttcaggtcttttg gactcg atacgg g a gtatttttaaatgctcagaagac agat gt tc cact ct ttatg ccact tgtagtatg tc atatagaaagaggtccacggcacaatccggcgcgo ggt a c a c aga att a cgc catga a cgc cgttGagtagtatcgcg gcaccgcagNtekc8o 25 1Dvy9e-nA 1rys8o p MRtty _T 6 9 L- 08 A G 3c21ctc gaccag c c tagaggtccaaa gaagaa g a g gtc c cccga ctc ctaa c c aaaaagtctct gactta g ggcg c c c g t gc cttcgaggaagttaa t gt cggca ctt g cag t g gcaaa a a cac c aacgtcaggcg g aagg aattgtacgacaactctctcaagcctaaaaccgtg g c g taccgagcattccgg g g ccccg tagcgtcgtgcg g gttacgctcggcaagtgtaatcgccgaacg aagtgccccccg gcaacggcaggcccccgatctgcag g g a ggccctcg g ccaactgtatcgccttatcctg gcgaag gcgtccctgatttcccc a g tac tgac aggagc tcgcctag g gcccatca cgcgaa c ccacgag ggg gtcctcc a ctggc cg gt ttgaacgggagcgctcacaaaatcacccgaccgcgttccctacg gctcc tcag agcgccgc tcaacg g gctt agaacgccctcct ac cgaa aggtgtg g at cccag g atgacactgtggattc cgccag gcgt aat cg gca ag g gccagtata5atcaag ctgcttgtagataccg ggcgaatgcatcgca cggcaacacagcatcct c ctccattgtcgcagcg g ggc atcagtg cgtg gtcg gcg gactgggag ctgaag ca caaca aggt4gcccg gg c c gcggcagc c t g c gtgc a t ac agtcctctaggcctg cc0gg gac0- c t a cgtacgaac gta c gt aga c c a cg taatcgaagggcgaataccctggt cg gcccg ctttt ctagttatactg ggcc attctggc9 gt ccgtaact cggt cta cg aaaccgtatacgcattatgg gacgtacaccgtg gacgcag ttcttagcaag ggcgac ta cgag gcc6gcggca cgaacttcaaga ctcccgcgcttgcactgcg g tggcgacgcct tt ag gatt gag c ga ttgagcctccc ac cgcgcacaaaa4tccaaatcag gc tc tggaccgtgcg aacgcg cccttc c cagga ctcta ttcgcc cc gcc atgtac gact ccgcgca cg cc atgagc ga71c0agt2ggt cgc cc g acccaggaattgcc cgcccaacacgtcgacg gtggcgaccccggcctgacaactcatc c aggtggatttc gtga ag gg accgca cc g acccctccatacattgctcta tcag gcctaag g gtcg c gcatttcaaaagctcg ggagtgtactactgcg gag c g t g:.aacattccggg accaatcgaaacgattg gtcacatg g gcacagtact cggtg ttcgtg g g ggacccagagcacctg gaccaacg gtcogcgccataag g g gactcg g g gccg gaccaccgtttagcg gaaaacagagtaccgcagcccaagaNtekco 1Dvy9e1nr86ott08 A 21atacgcta c g ggagaatctggtg atcgtcg c gagt acg ataattaactc t gccatcatgcgtc g ctgt ca t gttt t c ggcacg c a a gctg gtc cacc c cgtgcg aaacctcaccccgaagcgcgag g gtacgggcg g a g gatt ag g g g g aag aaaaggtgagg aag g g ggaacgtgaataacgacagag g aaaaacgagtattgcatcgcaaagacccaccccc g cctaatatagaaagcg g gagtcaag gtg c g gtcgcgact cccggccg ccgacattaagag g ctacaaccgcgcccg ccatg ccg gatgcgagcacagcaaactc agaaacgacc cgtccaagtccatgccctatccattt c cg g gg gtcctaactcaaagg g g gac aa ag aaaaaaaaag gtaaaccagt tcgcaggcg gt ctgtattgc agcgcgtcgaag ga gc c agcttacg gtcc acttccgccc cagtct cacgtggtct acgcgcttacgagcctt gaga ag g cacatgcgacaaacactctgcaagccctgcgcagcag acg a g gccgcg gcgttg g gacaaacgc agtcctgcctgct ccgcg gacc agcccgcaaggtac aggcat gag ctggcc5tgtcctttacctcgcccggtcggtgcctgac g ggtccatattag cca acgc aaaacggtt cgaaacacag acgtatga tcgc cctacagt40ttccgt0-ccttg gctaaactg gg tactagt c agctc g a gttccctagcaaagctttgtgtgcaaaagga gattct agc tca gg gaaacgcg ac9taag catgactgca agcc cactgtc g gcgctctc aggacgtccttgtg gct gaccgcgacg aaca cg gcct cgccgc aggccata64ccgctg c 7ttg g tgtggtggatc cagca c aga ccc agcaaagtag gtctcgcatgcga cgtgc ccaccaaaaaccaa actcg gatgcattgcacggcga agaggaaacgg a1ca cca aag taacg gccgg gctcaatag ggccacgt aa cg g ga c a c cggaaggttc gtc atgtt ag gga0cactgg gga a2cgcgagtgacacctcc gc agt cccaagcagact c tgctattggagt gc agaaaaagca gcgagatcttcatggcgaga caacattg g:.tcgt aagctgcactcc gcaccgccgcgctca cgtccaaaggaaatcgggaaaccatcgtgcc ccgttcctcgcaa ttcgaattc gctg cagcgga agg gtgtcc gcgactgacacc g ccg g c gacagttatacct ccgag c gac cc aagtcaataggtgataactgoatt c a a agagc c catgt c c c a a c a agag gc agc cg gacttgctcg gcaNtekc9o 25 1Dvy9en- - 1r1va86ottVF GR _T 08 A S 1 L 21tg g g g g c a a g ga gcgactggtt aga cg c gccgcgagta g ct gtggttttctg t a t tctccataac t gttttcctca t ttcag agctt ccctctt caac tagca ctccgctaaga ccgttaaaactg gtcgacaaag g ctacccttagc ag cag g g a g atagtg t g ggccagcaccctggtaattcagccaacgcgctagagggcag gtgaacgcttactg atccgcctc g acctcaaccgttaggacccaaatt cttcag gtatag g g attccg ttg gacagccacgtaccaaatta g actt atcaag gagttcctccccgtaaggtagct catctgg t ggcccaaagt c gt c cc ctg gctcgaac cttat agtca acacg gccatcgaatcga cagcgat cttgagtgcc ctcaactatgttgccgt caaatctcgaacgcagtgg ggtgctac tggagccaccccatgtg gcg a gccgcttgata aa caccgagcgaatg gt aacagtttaact cgcctacg gt cttat acggtccacgattagatcatcca 5tgaccaacgacagtggcgt ag gcaatgccccg g gtga cggagttg t gccattctcttatggagcc cggcgaatagc cggtatggcgtg atg4acaagctcaatagc cagcccgcgtgaaaccactccgggtcccggaaaac ca aaacttctatcatggaggca cgccgcacgc cttta cggctc0 ggcgtcatcat ccgaactatgc a-agc0 gcatgcgcgctgcaa ctcata ccc gtag cgataggtcccacgcgttaattaacgcg g agccgcctcgtg ggt a9tc agtgctcc aaaa cgctatattacacccactatagga aga agccatcgcgccattatcac aat atcta gt cgtcttgatgcttccg ctgta cgtag ggt cgctgtcacagagaaagtc gccgtgctctcagtttcgactttccctgtaaaaagtat caactccag cttt647ccat caacaacc g acaggagccgtctataagcccgcctgacaagtgaacgag gtc cc gt acag catgtcgattgag g gagctt atgtctt1a0aatt2tccggc acag gttg ctg caccagccg gccggatgcgataacccccaca agcc agagcttttcc a actctgg gtaac tg gggat a tg ggtgccac cgcg c catataaacatattgcgaggccac acaccaggactcttgacttgtgt cccgttgtaaa aattcctcgtaccctctcc.a:cgcaaga ao gta agtggt cgctacaattg gcacagcgctaggtc aacacttcaat c agtaacaaccg gtggt cctg gttg ggacccctagcagccactaatcag gttgagagctg g g ttcaacacccgcacgcgcgcgctattactt cgttacgccNtekco 1Dvy9e1nr86ott08 A 21g c gggt acg c a at cc gtccaa at ccc c g t ggtgtcccggtgttg gac a agctc at attaca c cgctcttggc a c c tccgatcttt tatg a t aagtcagcagtatagaccttg c aaacctatctgctgtcaacg g gaacccgcaagtg g a g c g tcg atgaacaaatataacctcaagggcttcaacttctagt ctcccacgcaataatccgctcctcaaggcgggag g c g ccccgcgcgtaag gacag g aaccg g gactaaccg g acgttgaattcttagccctcg g atcagatcg atttgaat cgttaagttgca g cttctcgaaatatttcag gagtgca cttcgc tgtgat t ctgagcg g g gagaa ctgaccctaga cctct taccctgcag g g gagttgc aggtacctgcctgagatg gtggttt cg gtcccaaactcattacttgtgtgat cagag g tcaa cctg a ctctcc cctg g agacaggtttta ggaccgagg gcagtgtt cgtgct ccgttgttttg g gatggtatagtcgtgcgcctataggaaag tc a5ac cacagcgc agccatcgac cggag ggcgcggctagccttg g tttagcgaccacagcgtgcggattagtgtg tcagt gcc agg ctt gcgg gc4 gtcgtctgtactggtacct tc agtgtccg gagcg ggagccgctaaggccg ggtttag ctccga tt agcggcggcttcgtctc agcttg 0cagtgg ggcctc0-tt tagcactgcagt ctc gcttgtcatcgaccgcacaaccaacgagaccctc ag gca agta ctctcacg ccgcc cat cggag gg gt9 gcc aggcagat cactgca gttaacccag g g cctacgcgcag ct ag agaatagcaatt ctaacgagag ccg cgtggcttgacgc tc6 g g 4t7cccccgtaca cactcatt aaga atccactgttcacgaa c agggccccctt cg tc c acgctccttg g attgtcctagct cacgaggtagcgcaggcggtgc agg gact cgctgctat gtgg gtgca atgagagtgtcactc actaatg g gggcg a g ggcggta gcga aac cagaaatc1gaca aataagaaa ccctggcgccta ctgctgaggatgagggcccgga ac ggtagaa tg g g cttt agaagcacggactgtcacacttccgc0t2ct cacttcacgcggtgacta:. cttg cactag gtctacg actgg gaa ac ctcg atgcg gtccctgagatttca atagaactaacat cg gggactcccGtt tcatcacgcgccttgagcg gcggtgcgaag acgctgct ct atatgatg gga ga aaaaccgtagaacagctgaacgcac attgcoaga cgc cgcgact a cgc a cga cgct agcacgtgaagagcctcgttg g gtaNtekc0o 35 1Dvy- 9e- 1nrysD 86o ptty BR _T 08 A G 1 L 21g t t ccgattggagccta ga gcgct tacatta ggtcca acgca ggc agtctt tatacc ct tccg gcctcgttt gcg c c gcagcgtggccgc tacgg ttccag c cacc ccattc c ccagtgcgctgaactcgg acctggatctaatccacg g g gttccg atgg ctg tcatgcatcg acgcg g gctcctattctccg gggtacacttgcgctccacgcgtttcatcctggaggacccgtcaccc g c ggagtacgtagcc g c g acccg g ct acctgataatcgaacg gagaag gacacaaccg attaatccacttaaaagccgtgtctt gccg acgagcgcg atg g ggcat ag tca tttttcgcgtg g gttgttctg gtctcg gtgctac gcccgtt aatt c cg gc cagcg gcgtaagaag gtatgata atgttccgttgg g g gggtca atattcc ccccgcatgttgaga ac cgaa cc gggc cg gt ctg atca cgaacggagtgca atcccgt ct cgacctgcttccaaaagtagccgt acgcgt ccc ccc gtccggcaatgac cgctgc acg gccgag g gcttg ccctaaag 5agac cgttcggtctacctg gtagagcagcgc4aa g gatcgagtga ataagag gctagttcgcgaggcacttg gtcaacatt cgataa aa ctcc cttcgtccctcac cctg g g gcggtg cgc tagaggcg g gcc ag gga0c ctgctgc0- ag ga ga cg cttg agtt gactttgcg acaaacca cgcc cgatcg g ccccgcgctac ca agcccag ggcgttgcgctcc cagag g gattt cg ggc9a tcgga agatttccaccatcgaggtg gat aagc ttcgc cgtctcct cttccca cg ggccaag c gacccga caatgta6acag a gac tactaacg g c g4tca7cc ccgagtttgtgcg ga acaagacgaaacaactaaag actccgcgtctttcgt ccgg ta tg gttacgt cgcgctggaactgttaacgcctggcctatgtag ctccc accacagt gta gggtg gatcg cgatcgtctc gcc ggctgctagcacgc ag1caa a0atgtccaacatcgcatgtt cgttgc cgcgga tgacac agcactacgtt ccatccgt cacttc ct ct ccgtggccctcggtatcgc ag2 ggacc:cccgatgaaaagc tttgccttgagc gtgattcga cctgttgct ccg gccg c g gcg gatg g ggcttcatggaacccg g a g g cta.gc gtgtcgtg gtg cg aag gat ac t cg gatga gtctgagggctcctgtaagagcgtctccgg gcctcgaaccgccccc cctg catgccoc agtgt a aga cttg gc cgacagccaataccgcttcctaccactacctcccgcggcccccg gctgcNtekco 1Dvy9e1nr86ott08 A 21c a c catt a g a c ctta act ataaatag a t t t t g ctag aatatt ga gtg gata t tcgcca tta cta t cccat ca acttcag gcaccgc g caa gtgctg cct atagc a cg ggcta caagca tat acc a ttt tg ttg tcgagagtgcgag g ttg ctaatcg ggagag ggaacgtaa ag ccg t g c g tttcacg tcg ggtacg tcgactgtcaggtc g c g ctgg ctaatcttacg c g cagcg g tt atctgacgcccg ggtg g aag ggtaagtgtatacg g g g g g g ctcagccatgtgtg t g gcgttcaccctg c g c g ccgg cattgctctccgtctcct ctatacac gcg cc c cg g ggtgtg gtgctgga c a agaatgtg gtttagt agccgagg g gttgtggaccgcact aaggacccccgaactatgacc ctcatgtacatttactcgaggtccgataaaatccacttgtttct gacagaccgta cccag ggcagt aacccaccatcggaaaacttgcc g cgaccgccttaag gaaacacgtaaa atg ata cccttgtacg tc tt acgcggcct gc aca ccgccag ca tccg gctg gaaccgt agtcccg gac caaatag ga a aa gcgtt agt tt tctcaattcc cccg ccgcggtccccccggtgcagcacc agga cccacttcagt cagtta attg gttatc5 gt4c cc cgtaagt cc agaga ccaa cggacgtgctccaa a agaaa acc0cagacc c a0-gcggg gatctacc ccacgaccg tccg g g gtc acgtaac atgaccagag g g c gt aacta ggacccacggtcgct tt cgaccgcagtta9 g cta ccctcgagccgttttcgatgattgtcctttacgttatgtcctttcg ca cacttctgt ccccaattac cgctgttcaagt ttcgccgttg cctaacgatagtccgtgaacaa aactcag agtaata ccgcgcctgagtac ccaaa c tg gacgcg gtatatgt c cat ttgt aatcaca64 g 7gccccaaccgacg aattgagcatatcagtacccaca ctctc tccttc acctg g gacgagtcccaaatttataccgtaa cgtaagagtatcg1a cc0g2cgtcg a g catc gtcccacaaatcagtctt ct gcgggtcgacggtgaagtcgtatctcagag gcgacccagtatgcgt cgg gtatgccacatggtt:ag. aggc cctcgc cgtcg gc a cg g gct cc ag ggtgagtcgttgtaccacaatcttgttg tgttcgccagacaaagatagtgacgggtctaccgtg gtcg a ggaataggtctc cgctgattgaacat aaa ag g tactctacaacttgaggtaaa cc ctcacta gtgtgacgtgatagott cgatg gc a cgaat agat aat a cat a c c cgc c a agagt c a cttgacccgtNtekc1o 35 1Dvy- 9eA 1nr1 oP 86o VttR CR _T 08 A E 3 L 21gttg atatc gccaagtaccctcatgata tttat ctgtc ggtg c aatt ttttctattt gtagttg tttcttgtatccatttaattgcaag c a a a c gactaattaac atac t acgccatcatcagc ta a cttgtag a g acct attttttacg gtg a g gttatcctactcaag aaacg gtttccacccccag g gttatccgtacagct ctcccgcacccttttccattaaccaacaccaccactttcagtgatagg aag aaaatatccttataccaagttgttcttgctacgattctccg g g gaattttctaatatttgaa g attgtcccacaccgataatcctgtacatgatcg gat cga a agagaattg gctctt c tcgccttacttctcg tg taatgt aagt gtaccaaaag gcgacc gcgaatgtcgcccacc cgctg c g atccta ccatatcta cg tttgcgagcg g gtcgtatagacgctttcatcc ctatttt cctca cctcagata act cgtc aaa tatgcacttgctcagc cgactccccaggagcgcacgagcctgagagaccg gccagttctcgtgtcgataatctgaccg ggccctcgattgcagc tcccgttgg gtcgtgcaccgagcctagtcttctgcctcttccgcg g5atgg4a at at caac ctcgaccttatcacta gagtctcgtgcgcctgaccgagattgttgtctcg gtctcct atgagtatattgcagacc aaac att0cta aa0-ccgatcccgca cgacg cagtaaag accggtccgtgtaggctcccccctcttctttc gc ctt caatgttcca agccaaaggctt ag gtgca9ccgtgaccg g gttatctc ctttt att actactatct gttta g g a gaacaatccgcggaaaagtgtgtaagggagact cttgt tggtcgg c g g a64ctt7tacttcgtaagt acgcccgtattatggatccatgaagtcgaggat atggagcaata tgat actccgag gctag gttta ccg atgcga cgtgatagttccgacatg gttcag g gaccagtct cg gtgcggaccgtga cttgatgggaataaggtg g gggctttgctcaata cg ggccacaa1 gtaccc0a2ccagat atttttaagagaatccg atcaaggaaccactagattagctgatcacctccccacattcc aacttattaacctgctattggagtt gc agaagaca:t a.ctg c ttacgctt cgctagcggt aggc tt tacgcct attgagt aaaacccg ctaaacaaca cgtccaaaggaaatcgggaoctag ga cgaaatacccattctttacggtagag agtct ctgcag cgtaagtcggtacgag gtt acgacctgt aggttacct aagcaaacagaaataccctgt acgc t cg gaagtatcaagacacctaaatacccgta cggagNtekc2o 35 1Dvy- 9e- 1nr1va86ottVF GR _T 08 A S 1 L 21gcggtc acagctagt cc a t cccg ttt t c gggcacg c a a t g aagctg g g g g g c a gaagcgaacgtggtt caacg c gcccgcgtagta g ctcgtc gggttcttct tag t a t agatcctccatacaaaatgcgaaagaaagaacaag cgacggtg g a g gcgttcctcaacccccg gctcgaaccagtaacagcgcgcgaatttggaccg gtcccctgatcgccacct agaccaaaactcagtacagcgcgaacacccgcg ccgaacccgaaccggcccgagacacgcctgcacggacgcacg gagg gcgt atccca g c g cccagcgg ctag g gaaga atggat gaaagt c gt c cc ctg gctctgacactca gaaagag g g gccaaaaaaaa aagct actgcactca cgcatcgaatcga cagcgat cttgagtgcc ctcaactatgtgt ccgt cag gacccaacatgac caga aaac cttgcaagacccgc cg atgtg gcg a gccgcttgata aa caccgagcgaatg gt aacagt taact cgcctc5gcgcccgcaa cggtaccagcagag ctgcgcc cgaccaacgacagtggcgt ag gcaatgccccg g gtga cggagttg t gccattctcttat4g aacacag agtatgttcgcgctacagtataaagctcaatagc cagcccgcgtgaaaccactccgggtcccggaaaccaaaaacttcta0aa aa gggattcct0-cc a cctaaag gcaacgcg acggcgtcatcat ccgaactatgc aa gctgcgcgct cgcaa ctc9g g aata cag ctag cgataggtc acg gcgct cgcgcaaggcca ctagcacg g g agtgcgttacc aaaa cgctatattacacccactatagga aga agccatcg 6c ccccaaaaaca caactcgatcatgcactcttccgcctg ata cgtag gagt cgctgtcacagagaaagtc gccgtgctctcagtttc 4gc a7 gaag g g gca gtt aggcagt cctcagcat ctgcgttgag gagcgacacatataaca cgg cg aa caag g g gccgttg gcc ctatagacgccccgc gcctgacaga g gaaa tgcaacccgaag cgatc cccca1aagca gcatt atgcgaataaccc gtctcaacgtg gt ct ac c ag g 02 acacatcggtgcc cccctt gcaaattcctgatttt cgccac cgcccatataaaca attgcgaggccac acaccaggactcttgacttg gt:.g gcoccca caaataggccc agttc agag gacgtgatttgctcaagctgacgcagcag a ga agta agtggt cgctacaattg gcacagcgctaggtc aacacttcaat c agtaacaaccg gtggt cctg gttg ggacccctag gccactaatcaNtekco 1Dvy9e1nr86ott08 A 21c t gttt c a t gtctcttcag agctt ccctctt a caa c aggactcc t c g gaccagttcatgtataaaacctta a acgag gctgaaa atcccttg gatcttaaaact aag g gcttagcctactgta c acaattg g aagacttaatttgtt g ctaacacccg gttg g c g ctgg gatacattgcaattcagtctctgcaccacag aattctccgcgcgcgatacacctatgt cc g cggatcatg g c g gacaatg ttacgttctagttagcgcgg gggtgttcg atctttcatag ccgttctcg atctcaatt cttgg ggccgtg ttcaggccttacatttaaggacg aaaagcc c t ag gc cat ag ga c aac a acatcatcga c agtg ggtgctacgta gggg gt agccaccatg cacccgcacgcg a ggcctatg ggtgtgcagcacgcgcag aacagcgaga cgaaagt cttat acg ggtcc cga ta atgaacatcc cc g g atg agaat cccgactag gtaacattattc gacagacaaacctga cggtgg gtcgtgcctcgcac ctgggc aagcaa tcagcc ccgggat tcgcgcgcgttg aaatgcatacagtgaacttctgtgatct ag g ccaacactaaaa cg gctcacgtac ag g a ga ca g gcaacg gtaatcttctgcctgcga cggt5cg g gacttggc c cgtagc acc ga cccgctaa cacg gt g aa agcacg40cc gacgttaattacgca g0c cg c g c gcctcgtcacagagc caagc- catccgag g c ggtaagagcgctgccgg gac ctt aacctaatttc ga ag gccattc ta cac a agtgatttaaagtcttgatggcaag ctgg g acc cccagcccacggtttgtg aaaacacgaaggtcctc tataaaa96ga tttccctgtaaagtat cagactgc cactttgatgttggaggc c4 g 7tctcgctc gcgagctattcct agacgaacacgtc gatacta gggccaaacacatg c gtcatct agatgg gctt attcttttcccaagcaaacac cgtaaaccgac aatac cg g gacgtt aagcgc a aga ccttgac1 gcttttccta a t tgg gtaaa cggagat ac g ggtccg cagcg g gccccg ctacacgaagctcg aaaa ccgaaaaa tcaaa caac gcactgc02ccccgttgtaaattcctcgta cgctctcacctt:. ag gtaccg acg g a gcctccagtacctcgccat ccg gtca ctcccgataggctaaaaacgga ag ctgaagaac gcgta g g g gccgct caa tttt ccG aa agaa aggaa gaggaacagta tgttg gtaccgccagc agacg gctacaag gott a c c c c c cgtt cg gc ag g ga cct a cga ctt aga agagactaagaacaNtekc3o 35 1Dvye- S 91nrysO 8o p_tty 7 R 9 T 60 L 8 A G 1 - 21tat agccgccgggcg t t gc atacgcg a atg tc ac a gtg c gcagaagattc g t caag a cg cttaaatcgagcc t ggc cacgctcg c c ggttaat tgcca c a a cgt ct ag g g ga ggt cc aca c tt ccggtg g gggcttttggtacgtg g cttagagagggat g cact cgctaaaaacatatcagtaagagttcacg g gagtcccg gaccttagccagctcatgcgcgaag accag gtctaatagcgaaggatgct agacg g cttttttcacgagtcataacg agcctcactacaccgcgtttcctt ca g cgaacagcg g ctctccg ccaagacaagtctgc g a g cta t c t c g g c atga a cct aaa agcca ttctcttgtgctga actg g gac cttgctaagatt cgtgac agctcgccttag ctgaacaacct cttgccacgagcacgactacg gtagttgcgccta cg gt tcg g ggtccagc at cgaagtgcacca cggattttg g g gaatatt ccc ctaagactt ac cgcgcttct aatcttttcg aagcc actcgaaacaagag c ggatacccaactgga actg t gctaag ctgtg ctga cc gcagactccc ggtt at ag gc ctaactg cctgcg c 5g4a agcttaaaggtgtc cg gttacacgact accg gctgttgaaggt ataaaaaaa a tcgg aagc gca c ca g gca agcc ccaataccccacgag 0catagactgtgtagtg gtcgggagaa0- g gttgt c caggcctccctagaacg accagca atct cggatg g gt acca agaaacttgttgcaccaggccgcg gct9aagtttt ca aagacccatcat cg gtc cgcggtagag tatgcgaaaatcatgc ctaacaag atg gctgcgga cgac g a ggctgcgccttc agag gcaaag ctg a g aaactaa cttggcgcatcctcacaaaagcgctg g tcacc cg g g g g tgcga ataagcattgtt6c4ca7ctctttagatattcaactgctt a cc agaga atagtacacgctcaag gtgc aa aattgtc tatgtcccaa tg gaagccttggc tcctg1ctcg0agagc2 c a ctgagagctgata actcgcgcagc acct cttt atcacaagc aggtatgtaccgcgattgaacc aacgtg cactctgccccaaa tggatcg agag gtaagaa cg gatacacacacgtgaaacaa acaaaggagatgcacagaacgcccaaacggttcgaacagc cg gg c:.g g gtogccttgc ttc agcagagtatggcc cgctttaagatg gatgtaggtgaaccatc cctttatgcccgg gcgttaagatatatcgggacccctaac cacg gtagcacgcgcacctgacagtgacaacaacgcgctcacac agc cg gtgatgagNtekco 1Dvy9e1nr86ott08 A 21cag ga tctg a taca cttttggag g gtgaatggcag atc tct c g a t g gggtatgattg atta g a g g aaaggacgtta c gagctc ac catc ataat aacgca a ctt a cg tag gt ttgatgttacttcca ccttcg c g a g g g a g ctccgggt cg g gcgcgttgcgcttaacatcgacacggagcaagaatg acggaag g g g g ttgtggctag gtg tccagaag ctaagcgacccctccacccagccatttcgtgactagccaaaaag g tactcagagactcggacg tcg aagaccaagaaatccag g gcgttacag g ct gaccgttggtgaaagcgctttt cgct cg gcct acgg gagat ag gaaag ggttgaa t cgt acctacaactcg cg ag acag atg ggg ccgccataaac ccctgtt tttg gc acaaat acacacgcgacctct aagtaacaat ccccccacgagtcttttaaatt ac g gatgcc aagt ag acccattatg attttaaatttg gag g g gacgagcgg aag cc ttt cg t c t tatgt cactt cc cgc cga gagc catgtgctccgttgc tc gctag acgagttgtttttaacaa ag caaga agat a t ataaacggcaaaatgttcaagcactttactgagt aaa agtaatgt gaaacag ac aagt cgtcgagttccacac gaaagaatgaggt5 gcc c c catgaa a cgcatgaatcgtgttta aag gagg t a gtc g ctg g4ctgg c acga ccgt tgcgaga atg gatttt agtc ttca a a c c ag g g0g0caa a a agcg - gacggcga agaag ggc aaattg ga9caaagtaaaaatgttcgtg g gtaacacagcctcagaa g caagat aggacc atag agttaagccttag accaaatgg gt gttcccgagtccaaacatttatgccgt64ctccg g gtcgtcttcg tgcaacaagaatggcgtg g gat aagttttttagattcctcata cgcatg tg aagataacactgaattttagttatag7gg g cgtgattgttac ccccgcgagg gtcag g g gtttaaggtatttgacacgtatgattactgcc ac acctgccttt gaaaaatatt aatta1c0atag2 ccg ggcagatggtgca cg gcga ctac a a agtaccg agaacttaccttacattg gacagacttcggataaa actaag aaactt att cta:cttgaaaccg.ctctg attg cctgtcttggcat agtcctcaaacgacgtt aactaaaacgtg g gatgtcctactaaacgcg gcaacatgtgtcgtctcacgac agg ctcc cagg gcg g g ggcg ggcccga a agtttt agataaata at tccacaatt c gtc atgtaaggacctacatacctaggo gc a t ag gc t tggtgag gat attatga att cttgaat cgt ag gagt cttg gNtekc4o 35 1Dvy9e- - R 1nryso p G 8tty _R 6 9 T 08 A G 5 L 21a aatcc a a g a gtatctaaa gttcat aagaaacg cg g a gttatt gta ctg a c c ag c gc cttatcg c gg c c g a t gc c tttcgtagag cgaatttaactag attt a ataacgta c c cc ct c c cttctagaattttcaaggtaggatcccacattttactcagatcgtttaaaatccatt aaag gag tttttactgttttgacagtaaatggcaag gaatgtccgaacattaaagatcgctcatgttaaaactag agacg gtgctaaag g atgtgtgaaaagcgcacgtacgcgaaag acatt aggttttacttcgttcgt cccaaaagaagttttgaacaaacattgaagga gt a ac ctgaaa c a caaa a ccca t ct c cagtagagaaacattttc ccataat acccc acagacaca ctgcggg g g ga cacgtcctta t ctcata tgagtct atgcg gaa cctcatt t agt agg tgaga ag gcttcg g gttaaccg g gaaattccatgataaaag aaccattttgtactgt ttttcaccgctttattggt agcttg gccat ctg taccaca5ttaaag aagtgattgaat c c4gtaatagtccg gacgagg gtgggttcaat atgcacagca cg gca gtccctccctat taacctgtca ag gtcccgct agact ttgaatgt ccaaacttttag aga cacacaacatgagccatt aatatgaggattgtcaccccacgc ac gt ccga atctcg a ggccc0t0agta cg-a gtcgagt ag gctattt cctcaaaaaaa ac g acgaagtttg gtcaacatta ggct tctcccc attgtacgcttga catcctcctagaa9 g ga aaaagt atgtagtcctcac ag gacgga tgt atag gataagcg gaaagcca actcagtccccctgtattttgctg gtattcccgta6 gttcc cg gtacttgaaatgtgta aa caacagttt gaatgt tatatctactacccttcagccccaacgatatctaatgcgaccacct gct ga47acacgagtggtgttttcta aagca ccttt cccttaccattttagacg cgcgagtcgt attttg ccagcccaccttttctacatggctc accc1atggaa0t2agcattgttgaaattaacgctagaatagaggattccacaagta agacgaggagatatggtgtaa cgcactt cacattg ctttcataacgtttt ttcg aactc agatg gctg gttacaaatgacttgcaag gtccag g g gcctg gcgcctactcacctttttccatattactccaatg ct:tg.tatagacaaaagaacactg ataagtttatcaataacgcatttcc cataagccggagacctctccattttaataacaccgtcgccgcgco gttctaagatgaaacttgcggagtgcgtgaaaaacgcgcaacg gacccccgccatttacaggag ggatcNtekco 1Dvy9e1nr86ott08 A 21gttttt catca at aag c atcttc t catg tctca gtcgtcc gaattatttttgtgg tt ct cta t a aaggagctccaca ag a c c a g g ggtgctag g t cacg g g ga atgttgta atgattct aag gcacaattgccttttttgagtattgtaacttttattcttggttcatatcttgtaactttgtatagtctttttcgtgctttcattatcgtt ag gtgtcagcacgac g cgtacg tctacagtgagcgtgctatctctg cactacggctccagctactg tcct attctgctacg ctcgacg caccctgcgagagccttt ccctccacctccttcatctaacccttcctcaacgtta gtg gata t ata a g a aagagcgaaacccga tg ccgatatctg actg ta aattcctc tgac att taatc ctt aaa ctgttccatag ctgctttcggcgactg ggaacagcgga cagtggatttcaaac cg cg ggtttactat aag tt actccgtttatat aagtttattgattattg cacagtgt ccgtggg ga c cgcacatt gaaaa aaat cctttgcccaagag gtc atata aataagtaatagttaactgttctgttcttctttg ttttgattcttcataa tg gaata accg gaccccatagaagtttcc acc aagtaat5gat4 gagtctattg acgtgtgtcgttgtatta ctagagagcatt gaa attattgcaatc gg gga cacgacc atacagatat gtttaagtggcaccac0caa0caaacgtgttgaatgtttc-ctg gttctta tttt tgtgggct catttgaaata ag ga gacttatcg g ctaatgataacacgcagcct cgatctta ataaacaca aaag ttatcttgttgtgctaaa cattctttcaggata cgaattacgcttg c g aaaacttggcttg g gacgcgagaacg tct cg9a6cact4ctttgt cctt cttttgtattccccataattgtg ctgc a acacttcattaataattatat c aagc ataatcgcg gcc caagccaaaccagactgcacgtt gtcgtcttgaggt attgaaa tgttttaaaca aggattaa ct gcccttcctccaaacaccg aattcagcctacgtt gtt gt ag ga gtg7c ttgc ta ttt tcgatagaata atcttcc aacgtc ttgagc aga cgag10cc2 ct agttgaa a aaaccctatgctcctgtact ac cccgacctgcc a tta a tttt:cgtgtatt.gt atta aatttctt agtttaatattt ttgcgt catattatcctt aattccgataacc catac ctc agccgag cct aaccttttoag gcatttactttcgactcacttctaatcccttggtaaaaga gca aggactaaaccgccggtccatactgcttgat agctccGaga acgaagc aggacccgtgaaccctctgtg ga cggatcaag g gcc tgctgtataatta cgNtekc5o 35 1Dvy9e- S 1nrysO 8o p_tty 9 R 3 T 608 A G 2L- 21ccg cacacat gccaa ctacgtatg gc tc c a g cgag c ggcg atat gcttacagccgcaaag ccgga aagaaaggc aac ga ct accg c a g g gtagtct atg aactgc aa gtgcgtacatt t tacaaggcgttcgcatttgtcttg gtctgagctaaagagt acgttctgacatt ctcacttatacttt at g cttgttcttaattgctttcgtggacctacttgcaaacaacaataaatg gactcgccaaaag gcccccacgtgcag ggtgttaccag aacag ctcattg tag tcctgaag g gcat agaacaggcg gtg cagaaag agaaacacatgcccctctgc aga cga cgcaaaagcagcgataagcgtgtgcaacctgaa g atcccgact cgtag ggtagtacgccccg cgcgcag gtt cccgtgagttgagcagtg g ggagatg g g ttt attaaaaac atactg ggt agaagag t ggagga aaccaggaggcc cg ggaatgga ct ccctaaacccgaacgccggac g agtgtta ctat tctacgggcggag actt gcttctca aatagtgcctgcg gaactccaagca ccgtacat aggcgcggccg g gacgttg g c ggcgtaccgctgt atat5a4 gactagagag g tg ctacc ccgcttccctgccttcgtccaccgc ccggcgaaaagattg gggag gccccgc a tcagagcgtacgtc cg gta0aata tt0cgactcct-gagtt tt caacat cccaaacgtgacc c a t aaggg gaagcggacc accctcg ccaaaacccaaagtgacgcatct caaaat9cgt g aa at caaaca cc g cactc gac aa g g gtacaaggctttcgaata cg gga ttcg ctac tg g tgcc tcgcgat cc agtagatt6aa c a ag gtagcc4a7acacagccaaa agc cggaaa c tc ctag a gctct cacag g gtag g ca aatga aggcctgtggagagtt cgaagctaacctatca gttggtg ga cgg1aaaataaccagcgggcacccgccccta aaaag cgtacggtg caaggcaccaccacccg ctaagaccg aataac at0aacca2actgacgtttaggaa g aaaatg g ggacgcggtattccctatactagagaacatc agacacctgggctttgattg gaatttaacagcgt acttg gcgt aagc cca caacg aaaaatc tttagtatgt:.ccagc aaaga acggg accgc g c acgggatggttg g gccaa c c ata gaaaaatagtacg acc aaattc ccacgttcg g ccctgctgtc g acgctgat atg tc ttccgcgtgaacttacg g gagcgcgattagaacoc c catat cgcatgc a c c a agc c cgcgcgagt agc aga cg ga acctaNtekc6o 35 1Dvye- G 9nry1 s C_R 86o ptty 2 T 0 L 0 - 8 A G 1i21gta gctttagtct aa ggaat attg ctat cttgta a ttcttg a a gt gcggacaat cttaataacacta ttctt a c aata cgtc caacaa g a c a aaagtgt cttta gttaac a t a gcgcgttatttcct c agttgttattaataaagcgctat cg g a g ttcccttaacaaaatacgg g actattttcat ag gtataat ctaagtag gtgccgaaag ttaaaaaaactttacagagaaagacctccttt g acgcag atcaaaatgtcaaagagccaag ctgtgaagtttctgtgtttgcgaaaccgagcgatatag caacgctactcattcgaagtctg g ccaaattatg aagct cctatg t t a tc ctttag gaata ca g acttcaaaacatcaccccg gataggcaaacgtcccttt aaaagtc cgacaacccca attgat gt cg actcgcgg ccagt acactgtttcg aaaaacc gt gatct ag g catcatcaaact aaacttatttttttttt agagatatgaagcatcaccattttaaaaaagtaac aaaagagt c aagtgtgtacgt g5c a acatcca agccggctataaaga cgaatccaagataa g gcattc tttag acttcaatcaagtttgaaccaacacctcttgctgttttt ccca4tac agag aaggcaaagct atttaaccaatggaa agaattt aacgtcaatagctgttta atac caggagttggaaag aagtcaggct ag agcg 0aact c0-ggctttcatttccactcgtacatatatca ctcaataagtctt tttctaatgcaat tattgta aata cttaagggtacaa agtactattaaa aggag a gcagcgaga tcacgtttctgga ttagtctaaatttg cgc atatt9gag ga a gcta cttcag gctagcctactattaga ca tg gc aaa atagaattcagcata aa gtat ct aatagacctaatcc cg acta aactctg acttcttt aagt agtaatt gagtagctacactgtggcag 64 g ga7g gttaacg ccccga caatt aaacagccaaagaaataata ag gtacttactcg aaa at t cctaaccgcaactcttgaagtgtag ttaaagctt1ag gtctt02 g tgtaaccccaggaat aggaaaccccatgg aaca actggtacccctactgtga cgacgcactgtgcat ac aa g act ccataaacttatagtgtacgcac ataccctg gcctttt ttccaga tacgt gag gacaaattaataa ac g ctact ataga accaa cgatg a gtaaaac agac:.g g ttgaccaaga gt ca a a att actgtgcggat catacggatt tcaaatatattgccc cacgaaagtttatgacgaaaagtgagactaagaaco g g gcgctactagcagtagcacgacaagacattcaagcaag gaatctaacgagaaagtaacagtacgtcaNtekco 1Dvy9e1nr86ott08 A 21t caa t atag c aaag taaa a c a g g t gatatccaa aaattt gtag t gt aac tttc t a gttgta ctatctaaaa t ttgtaagtt aatttatttcaga tt a a a c ctcatattaac aatc ctcttatgt tttgtc t g g gtaacaataataaaaaacttaacaactaaaaacaacaataacaaatgttg agtatgatagagataag gcttg aaataaggttaacatg ggtgt acaccaag ccgtaacacaagccacg ttaatacagaaagcaagtcacataaagagtaaag taaattctttagaatacatgatcgag ctcaaagtgacaagttg actagtatgggactgaacctgattgata aga tgt cag g gac ttattt aa a g aaagtcg tagtaacagt aacttaggctggtattgaa tgaaa agaatta agatttatttgtg c g atata aaaattagtgcatt a cta gtgt catcgctaat cgtcaaaaaggtattt aaatgtcgtgtttaacact atacttaatctgctcact cacatatatacta aaatacattagt tttacata act catag gctataatctg cgcaatagtgtaata aatagcg g gaactacatttg tttgagc cgcaaacg tt ctatgatgcagaattctttaagcgattaa cgatgag atgt5aag gggaccggta agcgca agttcagccg acacaacttt ccaaacg actt aaataactcacagattcaagtcagaaaaattttatccaattgactt4 g 0ataatgt0- gaaattcatt tg acgatgtattacaaaaaaaag gct gt acgt attacatatttttacca tatgtcattt ttaaatt agc tgtgatttg9caaa aaaattttaagttgtgt ct acattttctgtatgt aagtttg caatgc tatgtaaatatatgcttaaaaggagccaccagagtaatacgtga6cagttgtatactttgttttcgta aaacg ta cattt aaaa caaccaaattttttatat attatttaaatgtgtatggaag a g tccaagataaacc4t7cg g a gatatctcacag ccctta actc accaatatt acatc cgattggtt ccttaca agt agtaggttcctcattttgactgcttgttgag gtgc1t0aaattacattg2 gttaattaacctt atccggctaaact aatattcttgattttttttctctattct catagacaactttgcttgtgagtgcgtacattgtaaaagactatcgtattttg caaaagtcg agcatttaccaact atgt aatttatgcttataactattttg gt aagtg acgta aggagtttca:.gtoagacggc aaataggaacc atttgatttgcta attgatggatagcataagtagcatc caaaaaaat ctgacaaaaaa agtaactactac agttttatgttatttctt attt atattaagtggta agatg gttg ttg ggcaa actgaaagactcaa gagta agcaNtekco 1Dvy9e1nr86ott08 A 21attggattaa a cta agta ttt aaagttttttacaag ga aaa gttagaaat gaatta aag aaatta t gttg t g gaag t c gtagaacttacgct atta acag atcaaaaccggtc c gtatt a agtatg gatg ttttttgaaagttttaaatatttaaacttttttgagttaattttgtctatatattcacaag tttttaattat ataatacaat g a g gttccg gttatggaatcgtaaaaatattaataatttttcgtattctttgtgtatttcaaaaatttttacattttg ttact attttagt attataaacg g tctag g attacatgttttaattttatagg acatgctt ctctattgatgcctgaa g attaataaa c ac t c ga cgaacgc tt t atacttttat tgttctgt agttcatctt aaaac aactttgtgagaaa atta g gc agataactgaaacg acgg aaaaaaaaag gacactagacatagtaccagttcggaacagaat aaaaa gtatggagacct ttttg tattcg g gcaa aggagttgaatacc agatgctagagttgaattacttaaaccaaagtcggagtattg attaacttt caaatt ctagcgtatg tacttatttcttagaattg g g gaagtaaagagtggt ctt agtttatccg cac cttgtcg 5ccgta4a at atgga cata cgcggtgagag ggttccatttcattacatagaggagaagaca cctgtg t gtaaattacatcttaagac aatg taaatag gac 0agaag aatagcaagtt accatttc0-ct cat cggtg att cttattaat attgta a ccacacatctattg gttgaaatagagaag aaaaccgt caaattattt gactga ttc9t aa aagaa attaatt agataaca ttaattgt tagcgaacggcaccctagaaaag g gtgatt a a aacggtgaaag aa tacatt6caagtaatg t gtttgcaagcg 4gtc ataag aagta a a atgccc a taccgat att cctaagctca gaga aggc c tggcgccagaacagtat aagtaacc7 gattatt atctcttgattc aa g g ataacttcaata agaaatca agag g atc agatccttgtt a acgcttatcaataatt acacggcc agtgagt1ctttgtt0 gtgggagactcttca attata2 aaacttt cttcacta agtagt aa gcgctagacatac aaagcgttg aata aaatctcataatggga cgtttttaa gt:aggataga.Gatttttttgg gaa agccctg aaaa at ag aa g tagtaag aaacatctt tgttg cacaaacgttaaagtataatttcatg gcagatgaaatctagttt cccattcaaaaac acgtatgtcactgt attaggaactat aga ta tatt ataac aa tg g a gcctg gacg g ggcaggaaao Atttt a a a cttgtt a cgc aatttggtgc ag gc agc a a caaggagcatttaaacacNtekc7o 35 1Dvye- 9n- 1ryso pR 8tty GR 6 _T 08 A G 1 L 21ttccag g a gt g accacatca t atttattt cacttt at gtttacttt ccg a c ctc t t g g taca a g a aag a g g c gg g a gcg g atg atgtcg a a ggacacc ct ctgaccga c aga cgc c cga caagttcttaagttctatacag aaaacatcataagtg acgttgaat gaactaattg a g c g tcgtgatgtttaacaaag agcattg ttgttgttgcctaacgcttgag atctgctttttgtatatatgtcgatcct atagaggacataacg g g gtcttatagtgtaaacaccaaaag gaat accccttttctacg g ggtgttacttgtgtttatgccagatggttatta ag cggcgc agtc ccgag gg gagct a t agtt accttt aagg gtccg t gcg aattaatttcgat aact ctttttc aatcct ccccggatttgc ca g c gaaatg g gcgt ccgcaacggaaata cg a g gat gccgctagaagataa a ttt attttga gtaatataatatcactat aaagcgtg cacggagaatc a ataccgatatccggcag gc aaacccgtacaagagc a a agcg atatttgtttagcctttgtta acttgctgttt ccctga cgctg g gt tcca cgcagaata cttcc agcg gat ttg 5 gtt4t ttgtctttg gatttgacatataaatagttt agtcgtc cgtcacg tttctctgatcca agacac accgcaaagcg t gacaagtcc cggcc0att0g - gaataagaatg a gt acacgctgc tt tg g gtatttt attaccc atc atatcgc gagt cagaagaccag ctata acccctg agcg a g c gca tac9tactccac acta taagttagtc attg ccaatttctc ccct attagttaattaggc cgaaccg g g ggtaacagtgcccagacaactatg6c aacac4c ccagc aatacaatcgttgtcgttaa atattctg ccc ag g ccaaggacgccggtacgag g gcc cc aca agcaaacgcaa agtacgcctatcg gttgg agg catatgagcaaggatagtcaa tatcggcgcccg at cgaaacgact ccgctct cg ctctcctattactatttacca71tag 0a2attctg aatgtga cttt ctgg ggttgacaaacttctcgac attta caag aaagt t cattg gccaga ag g ccattccaagtgttagcttcacg attgaagcct:t a.gaa g gtaactacaagatgtg gtt acct ataaatg ctggatcg gcg g gctg cgcctacctgtaat cgaa accgggt tgacocaacacatacaatgccgcttta aa tgga ttaataaaacctcttcaaagcagtagatatgcgGag gttgggatgcccga cgcaa gcgc aaatcccagaat agcgacgca tgccgt cggat c atgac cttgtggtta agNtekc8o 35 1Dvy9e- - 1nrysA 8o p Ttty _R 6 1 T 08 A G 1 L 21aaacagtagtaaccctctcatcaat gctcatgact t actgt ctccc g t g g gtcctt c gt tctg c cataagtacatag a c ctaaac accttt c cgtatg tct ag gtggttt ttc atcctgt cttctga gtgt gaatg aaactacgcctg tcgacagccaagcgcactg ccgtcaccg g gctattgcatgaccttcg g gaaagctgttctacattaccg tataactcccacg g gcgccgtatg ggtccgatcacacctgtgaag gcattcgatgctgtaatcacactcaatt agagcg g g gagacattctg tctccaatccgacaaacataactca g cgctcg gaacacgc cctagga ttt ta a agacag ga agatacttcgatccgtacaatatg cattattcttgtaaag cag catcgat agtag ggccgtctcg caact ttgcatcgg gttg g gtaagcctg g gtg tcg tccctg g gtcttgtatgc cg ctgtaaaa aga gcaatacagct ctagcg gc caccgcttg ctg ttg gtgcggcagtcgccgtttcg g gacc cgacactaccaat ctcagtgatcgaacgtcctt agga acgttaccgtccttcgcct tattaaaaagttcgccg gttatagaatggcg tc5a ct cg g g gt ttaaaa t a cgtagtac agacgac aa aagtgagcca t cc4t gacag atttcc ct t c tcgg gctc agt a cctctg gagttt cg g gatg 0ag0-ccctg gttgtgatctctc ctaa cgctttcat ttgtgcttcacgtg agcttg g g gacgtggtg gcg gttttaaacgtgaccctg ggtgag9taacg acaacacaacacgcg cgtcaaggtgtc aaacccctcccgaccg gatacgataagtg gtgtggaa cagt ccgaggtcgatcgacag gtga6 g gcaacg gaa gtagtttacg gcaatgt ga cg ccccggt acgacgtag gtgtcagcgga catg gccattaggaggagccgtgttcag4ctct7a t aagcccgacaagcctt agaggtca a caac ctc aacaa ccgcatacaagcgg ggcgtt aa g a gaccaac gtag g caccacagcg gtt1c c0 gtagcc2 gtgtaattga cat ttcattcg g gaa cc gggatt cttatttctgaagccgccgcgtgtttgtacgtctccccg gcctggttggttaattgtacatacacgttgcaaaaat ccactctg ctgt ccctt aaca tactgcgtggctatgacttcgttacaagtaa ccgtg g g ggtgcc:.tagaactcagcataggtcg ct cg gacaactttc tgtg g gacgcga acgcc ccttttcccgtgctaccagtgcgact ag g ggttg ggaaaaoaag g ggacatcgaattagtgttctgccaagatg g g gctacgcgcgacagagtatccagcgtg ggtccNtekco 1Dvy9e1nr86ott08 A 21a atggca ctactttcca a ggtaatccc t c aag c g ggac c gccac ttaccta c g g a ta tg aga t a g c gcaacactcttaac tttc c g c g g caaccc tcac atta ttca g c gcttg cgagtactactacaccctcacgaatgg g gtgcattcg tcatcaagccg atctaag ccattgcactt attgcgtgagacctcattttccatcgacttctcg gttcacccatactctgtg aacttaacctaaaaatGg a g ct gtccaccgaagaacgcactg gcg ctgagagattggagtagcgcatcggcaccttaatag atg atg aattg ctagatg g g gt accc cc cccc agg ctat aga ca atgg a a gcttata ttcga act taaccacccgcggggtataatcgc aaacccaggccctgagatca caaaca ccgtcatc aa cggcttccctg gggatgcgc cgcattg ccaatagcctgc cg g gaagctcctcagtcgaccggccct cag agcgcggaacaacat ga agt ccg ggccaatacgttaaatcctttatttatgtcg gaag g c gctgcaaggaa gcgccacgacct tcg c g tccctcagcatttataaaacccttatttgactgcgaaactcattcttc5ctgaccag gaatggacaaccg g gaggtaattc c aga caggcgacagaag agcg g g cag a gatacatggattacttaagcgtt c cgcttatt40attacgaa0-cca9ca agtgaacgccgtttgtggttcgt cgtcgaaaca gtatagatgagtaggtttata g tcgc gtgcaatcccttagattttccgagccctagaatcctcttcgatcgacagacg c g g gcatctcctataggga agctg g g a g gag gtgttg aca ggcatccccctgt tgaat64acctcaact taaatgaccaggcgac cggacg c gataagccgcgagaga ccttccgat taacac c ag gctg gc ccttgacccgttga aagt7atacg tcagga cccgc ccggttcaat ga cggagac cgtacaccccgcacagcgtgctcat ccac cc gatttttg ggttcgatgtcga ctt10gt tt2tactgacgg g c gccga t a acg gggccgcgcgtaat caaacaagacgggtcg c gcgtaa actaagc cgtccgtcttc cgtgttggtcaac:.caactct a atacttctt gc ctaggaagaactcgactgcg ta tttgccgagtgagagagcccgtgctcgcgg g g atgagcccg attcaaagc a cg gGgtgcatgaggagtctggacattgcc gagaccg g g g gagctctcaaacag aacgg aag g gggcgtggtgacaagaggcccgocat a a a a cgct cgc c c a c c c cga c c c a a cgaggaaaacg gcatcgttgacNtekc9o 35 1Dvy_ 9e1nrMIM 86o T TRttA_T 08 A F A L 21ggctact cccg g t cta c g cttt gatcggcctat tcttg gaa t acttcg ttg cgtccccggtg gtcgta c g tatatgtc a atcaatagt aattagtcc t gcccg gtc ttagca g gttgct at aacttc tacttgtgtaaccgcg g gtgcattattg cacacg g g a g a ggctag ttccaagcgatccatg g acttaacccg gggca g cgct cctgtccaag ggatg g acacgtcg g acg cctctccaggaatg gtacaatgcgcctggaactccccacg ggcccctg g cctag gag ccacacacctgg ccgag aaactccag gctgttgg cctcg gaaa caagagcgt cgggagtta ga cg gcgg gtc acg a t cc c ag gcccttt aatgacgacctagcg acatcggag gatactt cacgtac g gaattatgacaat aatc ttac a t a ag aaatagacag gtcgatagttcaccag gctagacgca cg ggctgctgagtcgttccac a tga ct agcc gagct cttg gcctaag ta atctacagagtcctcggcc tgcag g gg catc aat cg g g ctttatg g gtttc cgcctcaact ct gtac ta aatgggcat agctgctgtgtgagagccccctcaacgggcttcaga ag gc tt5 g g tggattaa cga ccgttgctctccgc cacttttcccag g gtgtaaaacg a g a g cagtattgt gcgccatgagtcactaag agaggtt cgtta40a0-gctt cgcg ggcctagtttcctctcg gctg aataacagtgttcc acaaa t ccc gttca acatgacgatcaacgagt ccg ct tctccaaatt tcct atactaacctgtctagtc cgtgctctgctg tcctga caaag gg g gga ccag gcagaa agGagtg ataaagaacctctcactag a g g g g96gctcg g c 47gactaggt gtaggctcgtgct tccccc aacca ctggctagtgcg gtttatgaccctcaacttacaaca catccactgtt attgtcatttttg c gttgtcctg 1 gg ct caacttcaa aggtatccggttcactatc g t gg gccatttctgtacattcaggagtgggt c ag g gttg ttagtg gtcggccctcctcga atacccactgcac cgagcg gtta gtgag g g g tgcttgtgtg gtgatgcgt agaaccgctgggagat cgtttccc02 c gtg aagc act c ctagcgcgttaatgtg g g ggt agttt ctca atg g a ga:.gt t c tcggacctgcgttcctcttttgc cg ggactgcgtttt cgtg g atcga ttt cgtt atttactcg gtcg cctt gt caatgtgtctcacatcggagca g gttatg a gga ct taaatttccaagctagtg g gctoc cg g gcgttgagc cgagt c a a a cgc actga aggag g g gtcctttgagtgaNtekc0o 45 1Dvy9e- R 1nr1 mR 86o VttR AT _L- 08 A E 6a21aag gtaccgtatcg t gatccatagaa catttacgact aa atac a a g atatgtg gcct aat c gtgtccttgt cc ca gt a atcg aactcccca a a a a gaggtgtcat cg tctga t a tat a actaccagagt atcgtagg aaaagtgagataatg acgattttggtaaggaatag g acg ggaaaaacaaaaaatttgatagccaggtacagtct ag gtg aatag gg gtttacg aacaggcgtgagggaa g tagtagcacggag g tgcacggtaaacg g taaag g gagagagattg gacgcg aaaag acaccaggattaag g aagtcag ttcag g aaaattttgtaaacac gtcagtg gc a t atgcgaaatgt agt caagccc acg gt gaccgacag cgctgaaggcttctgca a accgct ccatgacttggag gcacata tggtggt gcccgtgat gaaa atagccgttagtatgtagccag g gtaatagggcga cgcg atctacc agtacgcacac ttcaagagcct ac gt gtccgggtaagcacga gt agtggt at acttata5aggaagatgagaaagtatatgagtt c ccatttgaatg actcaaaac aaggtgacccgtaga aagtat cctctaatag gacg gatatgaact cgga4aatctc aacccgtcag ga taccg acac cactgcg gata ccgtctctttttcacc aaacg acaagttt ccaaga a cagc c ttgac aact0 g gg ggct0-actaacaca acg atataactaa agtt atata agcaattagccgcgga cctaagtcttaa agaacaatgcttg ga acaa agagttg gacgtactcg9taaag gag agttttct c agcgg gagtgaatgactttttctccatcccagatacaacaatatttcac gacata cga gttactttaaaagaaaaa agtaccaa aggcggccac ga cgttt atgctagcacaaccgcct act cacgatttt cacacaagctaacaac gttga64atatgaaaatctg gaatagtgcctaaggctg c gattgttgcaaggac cgtccgatcac caca cgt tt caaag actagt at ccat cccaac c71g0aaa2 ag g t gtagt ccatg gtgatc a ccctata gttgttcgtcaggta gtttacccctcgcattc tag ttgtcgttcatg a gatat agtgtgcgccac acattcgagtga acgagttg g g gtag g gtcg cag a gg ta accgttatt cttttttcaaaac accg g acgtgcaaaaacaa ctcccc.c acggc agtg accagt gt ca t ac c accgaga ttagagaagcct ca:cgaotagcgagac ctgga acgag ga cggtcccctcacat c caggtctaa aatggtat cgctatttcgaaat agaagcccact c agtgcagc a cgaagcat tg ggcaagtcacaNtekco 1Dvy9e1nr86ott08 A 21ct tcaa g g t gtcgtgct c a cgagtc g g t ggaaaccgcagtcttcct cag t c cataaaag atctaatcaaacactc ctctcaat ag gccaac gtg agcgt a a at c tt tc ttt ctga catgt atta attaagtg aggatagtag gcaca g catgcgt ag aacag aatagctag tag gccgtatcaggtaatag aagg acttgtgtcaaaggtccctacg tcg tagtcaactaacg g g g ttggccaatg ccctcagctcttaagaa g atgattccgggaaagtgattgca g c g gtacctaaatccccaacatataacaatgctacg g g tctagtcagatgaggttagtg gcag aaaacctcctaaccgagg agtaaggt aa g tattttgattaaactga aaatca g c gctt c c cgctttcacgatac ct ggccg ccg g g gcgatct a cttgtcg ttttt tcttcat c g ga aac tcaatg g aatc aac aaaactcagcgatgctt gttg atactctgagatctg agttg gctctatcgatgtttta ctgt aaaa cgc atcta ttacccgaccttt gtgacgatgtacgatgcaggtgg gatt a ag g gattt agcccctctattaccattttgatccctcaa acacgactg gaagaatggt catggaa ttga5cagttatttg a gccgccgtaaaaaacttt ga aatgtaaaggattttaactat tcttttttctgac cgtcc cgatt gt aactcttacacacgtcaa40 gaccct0tgtaaccg aagaggcg -gccacgaaaa ctagacagataaatccatc agtattg atcaaaactcaca agca ttactatt agaccaaaatcgtct9aaatacaaccgtgcga cttggtatacagagtccgctg gaatttgtcttccct attg aag ctaccaaatacta agctgtctag caaacttt gt6 gc4 gccccaatcaagccatttgc cc tt cct aacgactatgga cagct cttt7tctcgaggcaaccaca ca g gagag gtatccctgttcgaa gt gattact acaaga1 g g gcgacatttc atgtaatggagtca taacaagtt gttttg agttaatattgtaag atgttatagct at aaat cggta aaagtccgt agcacccttacacgaaatacgagt acctg gat cccg gtttt tg g ctaatc aa gatctc tctgttttccata catctct agctagtca0c2c agcc cgctttca:.cctgtagtggtt a a tggctaa aac tccctcaaatttgattttagacaacttca aagagtttcaa attgactaaatatgt accag cccc cgttggg atgagt gtcctacaaagatccggt Gtggtgaggctgtac ttctca g cacccacccca gtgcg g g g gatatcattgttgoaatttgag gat attg gag gc agctgagc a a cttga c actat c aat a cggtNtekc1o 45 1Dvy9e-nryB 1 s S_R 86o ptty 6 T 3 L 0 - 8 A G 1i21ccacta aact aat a t gacc atttaatat acttttac agat t g c gat cctgttgac atga acac caag ggaaat tt cgcag atccgctttatgaaa ag aagacc tcaatgg gca ctctctagag catgaagtg ttacgatccccacacccg ataatcttt aaatcttcaaaaccctaccggatg ctgcatcaact gtcttaccagaaaaaatgagaacacttagtttattatcacgttttatcatcag ctaaatctctacgtg aaacggtaaatgt aaagtaattataacagact attcaccg t g c g gtttaatg g gaacag c g c g gag tcgtg gttctttaattga agagttt cg gcgc atagacat ct tattgtgagaaa gccaa aagaatttcgttaataaaagtg g ctaatatatatcacgtgattacaaaagctg ggccaccca ac tggcaaatatca cc tcaagtacaaaagagcct cccgtggacttcgt ctaata t gtaactagtagat aa cag gctg tgtatgagc tgccgccggaat ctattt gataaaccgtaat gaaatg gtcgttttgc gcgaataatcgtgtt aagcatataaa agtaattggc aaaacaga agaag cagaacctatgga atag gttttaaatatc ttttgagat aacagaatat agcag gaa5a gcatacaaacggtacg a g atct agcaacgagaggga cgtag cgtcc atcg atggaatcgg aacattatgtgcgtc aggtctctgacgattcttt a atg 4cc ct0agg0-gt a tgtaatg gaaa acga aaaacgtatgataatat a gacaccg aaacctctttgag gtg tactgagtagaccttgaag gt atctaat c ag gg gttgt agta atctggggtagcaaagag c gaggag ctg gctgcccg accggcgtg gctgagttttcc agtg g gcagccacggat acat actag at9cga6 g4ttg tgttttttc agcacctcgc ac ccatga ct aaccgacaaaacag gactt tagc a ga aacgttaaaaacatcg gatattagcga aaatt actgtaccc7attaccc g acca c cgctctaagtaa caagattgagcccccatgaggaaatac atat ataccca agag g acgtaaccg gagtacccctctt1ttattcgt a0ac agttgattcaattagaccg gtgaaaa gaga ctacggcccaaactcttaatagtcagcttagaacttatgggcgatg ggctcttctcagtaactatt gt cc gtttgcatagag ggaga cgtcatatc c actcttcctataaaattcgtt attc aagat atgacgggagaaat atcag tac2 t:t.ttgtota tcttttcgaggcgatg gtttgacacgttag gaggaacgc ta gcag gcaacactg gtacctttt ac gcc ctcccccctg aa tgt a agcttactac cgatgga tag g g gtagtatc agaa cgtacag gttgaatatcgct gattacg gccacta cgtagctaNtekco 1Dvy9e1nr86ott08 A 21aac gaacggacttg cacccatta cc aacagcatg gcaat actc gtg a ggacttcgat taga cattcg g g agaag aacta gttcat attggttgtc t t gaca t t t c a cgtggaaattggt cc t aaaagcgccagaac ataaatct cccaatca acctacgaaacatgttcgtatgctaaacacaagat tagaatat aaatag gaatg g g g cttgaaccgattccttg ccaacacacaacgttaatcgctccaaact caactcttcact ctatttatagacag g gtgtcagacaattcgtttaaccacaaaaaagctcg atctaaacgccgagcccg gcgttcaaaaatttcc ctaat a cgatgaat ag gattgagaaatctatatttaatagttcaatttgtt cagcgcgctcgacccg gg cccaatacacc ca g c gaagggagtcgtcattatt aagaggcctgt tcttcgagtaaattcttactt tagcatag caca ta cttatgttt ccctcaggacccgc agc tagtgaaggttatgaag agtaa ctcaacat tcg cagttaatt5cataa gttttacttt atcgagtt atga4c ac attcact cggtg cgaca cggttt atcgtacag agc aggaattcga ctc aaaaacttcccgcgtagcaagt gt cagc aatcctaatg ctgt ctcaa cgcttccagaacg ggtccccccatgaaaaatgaga ccgct acaca atccttaa c tgg gt0caccat0atagtgctgaagcgatacc aacgc cc c agacgaga agtaagacctcgtccacacattag gt aaatacctcgt ttg agtgacttgc- agtccttttt atagtcagacggcg cacgcg gtccatatccccttatatc ctttca cgc gct cgca aa gca cggtat acg acaag gcgctga96aa aa4 gcttt catgaaaaagcacgctacgacttccgtatcatctaatttacgaagaagagcacat ccagaaccg cc a a agactggagc ga ag accgacttcccatcatgatcgatccat cgat agataaccgcc ggctccttagcactccgcaaaaga atacaaag ttg gataccgta agag ga ag7acgc cac a at a g atgcgtgactga a aggtatag gacga tcgt ga ag1ac0 gaa2 aat ttat aac a ct c t a tctcc aaatctga caagct at c cc g at:. cattat ataaagttagtg ccag g gtgaaga atcatccc a atttagccgatt agacaaa g ccattctca cat aagagcgatgtgaaa agcg gg Gaactataacagtaagcc cgcgccgca g a gtg tcaa at aaatac a cac c caagag ggacccctcg ga cca a cattga c a cgc a c tgttatoaatct a a c c cga a c c a ag ga a aatct ag g gc a c act agatctctcacgtcNtekc2o 45 1Dvy9e-nrysA DR 186o ptt_T y 3L- 08 A G 1 n 21tttgtgcttcgtaact cggta ttcgttt g g c g c a g ggggcc ggttagcctcagaccacaggcttcact ctcgctagctccacct gttctt g agt agcccgaagt ag g g gctgagta aagtgtctttcaaagcgtgcag gtcgcgt attgcg tgacctgttactaaacccccg g gcttag gttatg gttct gtatcacg cttttactcacataaaaag tcaca g ataaatatcctttctatg caacgtcgcccattctggtcacgcg aaccgctg g cttaag cag agccg acatcacagtatatg tcacatttgatatagcttcgcccggcgtgg atatcaatgtt cgcgcgggatctagctgattg acaag aaaga aagcgacat aatgacagaaaaaacatgcctac aacc cgcccacc cg gttagtgg c gattcatag gcttgt cgg aagcaagcg g c c ggcg ttct aa g gtgaacaataagt aaga cgtcgcgact a cg gcatatcatcagccatatcaatc tgactctaccgag gg gcccg ctaccattgat ccaaaattaacgctgatgtc cg gg gccaagcccttagcgg ggcgac atctattgagct gc attaccccc c agcgg gaa ccc aa g c54g ctactgataatacgaagtcgcgtccagtggag g g cccatggcgcgactgctaatgcaagtgccgtgaactgac cagcacgacggcacac0c at0aa-tt agcaattac gggtactgaattcccg g gg ct at g gttactatgccaggccaaggag gagctg gccgctgccg ta cgcgccatat aggcg9a g ac cgcg accg gtcgctc cactcacg gtctt cttccgta gcacctggccggt ca a ctaccgcgagaca cc ccgaca atgatg g ga6agt at4acct aaacc cac atctctgagagatcgcgtgcc cgtccagacc atcgc agg aa agcactgtg ggcggcagac gc a caagcgcaccc cgccca aga g gcctcaatgcgccgcagccag c ggc at ag cca cctccaatc cc g tacct cgcggca gcg atgc agtgccgtcatgc ag71cttaccaac tacaggcatcgtg ccccc ag g g cctaac ggca agtacaacctggtccacccg gcc cgaagt tatagccttttcacgccga02 aca:act.ga ct agtattccgtcatgcgcaccca gcccaggagcgtccg gttgaaggt cctgg cacctacggccct ag c gctgcaaggtt aggcagt cg g gttggtctca g gctg cgc cg gtatagtgggaaagca atgcc gcgtcgcagtg a gaatgacga ctgag g g gag aatc caccgcocga actat c c agcgcg gct c a cga a c a cga c ag ga c a ag gcaagtNtekc3o 45 1Dvy- 9enry1 s C_ 86o ptty C- 2irR T 0 G 8 A 6 C L 21c c t c ttgc caag gcaggtg aca cg tt c a c c c c a tt tt g cccctgtcattccc cgcgaaacgcgctcc atatgcaag caaggc agcg g g ccag atg gcgatgcag ttacgcatgcgcgtggacgccccg gtcgcgtctacg gtgcgctaagccatgagaaag acg ttaagag gacactgag g tcg gataagcaaggcgtgcatgtcagacatgagccctcgag g c g ctccggcacatgcgacatccagccaaacggaacagt cgcagttt ctat ag acccctg gacaaggcaagtg g aagcgcgcg gtagacg tctcggcacg cactgacgcctgcgat c agcca cg ggcg c tcagcg aag gctccg acggctagagcatg ggtgatttg gtttttatgagaggcgaag ccacagcacacggtg gc cgtg gcg gcc catacgccacggccg c gtcgacgtttg ctgaccacctcacctt tgcgcacggcttcacag g gattgagcg ggg gagaagctgc cggcttgggcttggcccg g g ggc5ca tag gcg ggc accagc taacgcgtgg ggcgccgcaaagcgcgttg atcgcggag gcgcg ggtccgaga cc ggcg gac acg gcgag gact4 gcaat cacaccacatc tccgcgagcaat tttgcctcctgccc ga tgtt ac cttcctcgttc cccgctgc gc cgctctcgcgact0cacaggtgta g g c gcagtgg ctgttacgcccgcca atg gc cg ggcaatg0- gagctg ccatg gtgaacag g acttggcc cgcctag ctcagtcccaa cggt9c aatagaggaa cg gtcggtgcaccgataccagaaccctataagcaaactc cg g g gtc ag gagga cgtgg gcttac cg6agtaaag ccaac cggatcg gtcgtgcccgctcg gctg g ggga cgcc ctcgcagag gatcgcaccga tgggcgcaagcctcctctca4tagcgctagtcttaa agatgaa ca agcccct ag gt gtg g ggtgcggcctgcg gg gac cgcgaa ctctct agccgc agc ctgtag gttc7g1cta ac 0c2aggtgtttagg gaggtgtaaagtcctacggacacctcaacatcccgggcctaaacctgc agccctggcccccacgc tg ccctcg ggcaaccg ccag tctaccgcgcgtgcacatcaag c g g tctcagccag cccttaaccgcg aactgg cctcaacgtttacatcagcga:.gcatg gggctg at t agaggcc agattc a cgcg g g gcc acgag gcctagcccctcccggaacag g g gtatcgcgatcg g g gtggcaco g g gcct cgtg gcagtatctcg ggaacgcgttacgcagcg gctgcccgcccgcgcccctgccggcNtekco 1Dvy9e1nr86ott08 A 21t cagcg t a g g g cagct aaggtcacac ct atttctaaat cctaga t c a ac aa c cta attcttgtttcgtag c cgggatttc c c gacatcctc t g ccgccct cacc ct tgg a a gtgtgc aat a agcgt ag ccgtccgcg g g g gcccg g cagctt accggccggcgttgcaaatctgtaaccg g ctcg g g g gccaatagctgccg cag ggccg gaggaggccgccgtggag gcg gccgcgtcccg gcctgggcg g ttcgcgctatggt cgtcac g a g gggtg g g gcaag g gcg gtta g cggcg g gcgcag gctcagccg ccg gaacagcc cgcgtcc gat tattgtt g cc attaatag gt cg g ggagtatcgtgtctgacg tagtaaaagag gggctcgcgt cgcactgcgtctg ggtaaagc agtgcac tagt gtgt atgttgac cgtgacaaata g g gaata ctagataccagag g gag g gat c ccg g gattcttttcacgcggaca cggtat ag ggagagttaaaagtg g gcgtacgaaatat acttttggaccaaacgg tcg gttggctgccttcccccaccatttgaagagagtaatcgaaggtt gttccaggtg tcc aaacgtgactaa aaatg gggtg gactaaaa5t4cg a ggctg acaacgtatggcgcacttt tttcagga ttg ctgtga cac a cgctgt tc aa gtgctatgagactgcttcttg a gtgctgactga0tt0-accg tt agaaatgcgctgcgagccggcacgtggt ct taaaacca aggttaatact gcactgagctg t gctctga agc aattg ttggatatctg g gccgatgacaacgttctgtc attttccctct aa tgga cctttgattgagacga aa g acgt ttccgtatttg a gcg gacgagcaccg9a6 g g 4c7tg ctca tcg aagc cg g g c gcgacttggtacgctttac aacgcg gaggatacttacctac agtc agacgaaac agcg gccgtct aa tatatagctc1ccgt cggaatgattgctttcttaata tttgccgggagt aagg c g gcaaacttcactttttttg t g g gaaa a gatttt acac cgtagaggc cgtaatggcgagcgc tgtttcag ttcacacgac g tccg g ttacaattaaaagttg g ctgt aaggaaagaagatg acgttgaacaa0g2cg:.ctggacacagcccgctcactgcttcc atgatgtaatattccatagtcgtccg gttg gcgaatc cg gt tt att ctt agt agaagtacctaaaago gccgtg aaagcg ggcgt cggg gtccagttGaa ttat aatgccccagatggcactagttag agtacttattcaaccaaaggcgtttaactacaatcg g gaaccttt ctta atctgctcgaag ccca acctcagtgNtekc4o 45 1Dvy9e- 1nrysZR 8o p_Ttty 89L- 608 A G 1 M 21gccaac tag t ct attga ta gtcacctt g a t tttatcggt ctaccag t t gcaaaagt aaa c aaa cat a ctgcttttgagaag g gtct aag gagta aagtccattaatctt tgc c a cat agc ta aataagaagtatcctagag gaatactcatttcattcagagtctattattccgcgttcatagatgt gtat ataagcgtaaaccgtg tagg g g actaatatacttttttg gggaccaacagag g aag c g t g gcg ttaactgtaccttgtactgcttgttttt cttctccaccag ggtgagcattgtgcgtttatttataatgttatgttattctgattatg g ataacg gttagctcgatgaga a att a ag gctg ggcgca a ataag gcga atatg cacatg ttt ctct tactctcaccgag agta tagactttgaacacttatctt ctactaaatgcactctt gagcctcttcact ac cacgcgccatg gtttc attaattcga agg ctgccacattct tttcag gt cct gaccttagccgcggttt ag aat cgccg g ctgagtc agtaagttta gaagagttcctgt5c tg agtgattgctgttt gt cttaatcgagttt atcttt tcc atatttggctgaagaatc cgaa aggcgctcgtttttcctgagct act att4t at agagaa gtgaac agttagt actgtatgct aacgttagtgtttttg actta tc gggtgg gtcg aaagt tgtgtggtgtt c c atgtaattat0agtaaa0-a9ctaaatcgttgagc a a aaatataa ata ttt agtctt cagtttg a g gtctcttt cg g g cacaccacgtgaagtttatcaataaactacatgaaacttctaat ct ctgggtgacttgtc cctatt cgg g g gatcctgggtcct a cgttaatcg gatg aa cggc agatttattgattgaaaaga6ccgcaag gt ac cggtct aaaatcatgtata4aaggataa cgcccg ctatgccttagatatccattgtattctc agcttcg a g g c gac agttgtta taaaattagtgg atgcgc aaa taccaagaagattcttgctggatgtg atacgtta cgtaatg ttctgagcgttcgtg gtctactat ac atata aa71tcct0 gtgtc2 gc aaatg atctcgcat g gt cctt cacttaaaaatta cg gttacactgttgtttacctgtcg aacatgc tcatgcta aatcatt aaaccg tg:aggc acttagtct aatggtagcccgcgctgc ccaaac cagtt ct ccgt caccttg atg g ctg g gag.gagg cttctttcatcttctcatgagt tataa g g gcatctta tt tg gtgaacctcg g aacct cg g ttcgttcgct actcc actaagtgca cagac aacctggcataatttgctca tgaao ga c a a ctt a agt agagcg g gacacgctg g g g g ggcgttg gcattttgaaatctaNtekc5o 45 1Dvy9eA 1nr-o L DR 8ttE_T 6 1L- 08 A B 2 n 21gca a ctaagtactcggtgaaa atacaattgtaaaa cta a aacatta t aaaatgaaagataa tatgttattaagaagttc tcgaata c gacacaatcc ctgaatg attgatttcggaaac c a ta cttcta tgcacgagactaag g c g gtctgtatataatataatatta aaataataaaaaaataaataatatacaaaaaattaataaatttaattaattaatttaataaaataaaaaaaag aataaaaatatttcaagaaaaaacatatgtccgtaataaagtatacaat ataaagtaagtgtcacaatagcaaataaaaaatt atgtactaaaaaggtgcgtttaacatac aagaaaga aagaatggaatttaaga a c g ag tgactaatcattt gaaaaactgtgtaa cgctattaaagatt gca tg gacatagttag g gaa agt gtgc cgaagt att agagaaaaat cgaataccacaggaa agag g caataagaa atcataaa gc ttt tttaagtatttttagggtgtaaaaaaaagtactgaaaatcttaaa ctt cttaaacg cctgtag 5gatcctgtcggacac aaattaaat ga ctacctatgtt ataaaagataa gtacta tgtttaaa cgaatgtgtctattacg gattagt ctaa gacccaa gt4ggaatttc a agag c g gt cttt attcattt cata tgcccat caagattag t gcacc atcgagtaagacaag t gcaaagc c cga atctttg0ca0-cag ta a cctattagtcaaaaaa tggcaatagt caacttgtaca tcgatatatg gattaaagaaa attggaaaatacatgatgcgttatt agta9at a cgtata ttt cccttgtagtct aggtgta at aat ac cgatccag gtttt agatactaaagtcgaaagact acgcaagagtcaaatttcacg6gcgcacagataaag ccac attg ga atgtcttcgaataaaagttatg gctaaattgtactttacgaatta ctaatgaaagtaaaaacgattt4 gct7 ga acacttttaactt tttcgaccatgt gtaccaatt aatt tg atgtattata aa tg gtttactgatacacggttcatccaaaagag gaaaa1tt c0g2tataag agtcactaa aatacgcagtgattt agtttatcacttagaaatttacc ag gacgtgtgg gtctacagatcatga acgcgtaggtgat tacaaa g g aacgtacttgac ag taattataactt catgta acaagacag t gatctgagctgg aaa taaaagaaacataaa gaatg gtatcagtagtg tag ctt atgattaatat ca gct gataga aaag ccgtata:.g g ga ct agt a tgtat c t a tatg ga aaa c aac aaagga a a c ataccgott a agcgacttctcacacgtaatttaaaaaaaccg gaaaagagtgatctgcagtagtataaagatcg gaaNtekco 1Dvy9e1nr86ott08 A 21ttacc t ttttc ataa cta a agacttta t gaactcaaaagtaggcaaaagtttgacg a gacaggttgagaatccctag c c tgaatc t a gctatg catcacgactg a tta gc tctt a ttt g aa agtgatg A acA caT atatgaagtttgccca g a g gatcg gataacgtgtgag g g g g g atttccA g a A attTtgctttttgatagcgatttcgttag aaaaaagaggccag gagaaaacagccggacacat caacactccgtaaag gatgagagatt agctggacaaaacg gaat ag ctacccg gcgatg gtgaaggactcgataccgttaaaccatctaaaa ttgg t aagaa ta a att a c a cggcacaaa aat atg ggtgTttgacgaggTa gtta atacacacg ggc tt aatt caaaa atatagaaacttgtcgttcaccatgtg gcatcgagaatc agga ccct cgacaagcgaa aggtactaaccg aattgagaacatcaaaataa taaaaga cgtgttc agaaacc ca gacgaaatttgcgagacttaccgaaag gctgatccag g gatgttaagtaaaacggga ag g ggtaagttgt gct cagtttgattat cacgctcagat ag gactagatg g a gcggaacga actctg5tag4 gattcaatcatagaaaattatt ag gctaaaatatttc gaattgataaga aaaaaattgag gttt gtgctttgatcatgaagcaatttatcctcg taagaac ctcgctgttc actctgcccgcg gtg gttga taacc0a0-gacc aAa acgtagct cattattcgcg a aagt aa ttggt c at atg gt agagctttaattt aag Tagacaaggaattacaaaa agtttat ac ccgtttacctt tttcg aagaaccacgcttga cgaacttaggtctacg96aa c4atgttgac7t atct attagcg a gatgatcgtagcacaaata actatatc gtggcctacctgaaaag ggg gag tacacac aacccattaagttcgcgttcagaaa cttacg g g ga acttagct aag aaatattaaa gaatattgtgc ga a ctcctctagtagacaactg actcg cactgcctta1c0taa2 tag ttctacaaccaaaac cg g gtctgtccgact c catataagatata ag gtttctggaaacaaa ag ggtat cg gag gtattctgtcg g at:.gaaga tt gtGa tgcactta ag gcagtagg gataatttcgtcttttc atacagtgctgagtt atcgatag ttaatag g g atccg ggacaaacoat agaaatctaAtTcaccgatctagaaa aaaaattggt tggaattccctctagacctaagaatatagatacattag gGatttcattgtcacccaccgtgtagt gtcgtgtagtgctgagaggttc a agtg ggcgagagtgNtekc6o 45 1Dvy9e- 1nrysZR 8o p_Ttty 47L- 608 A G 1 M 21aat gggttct act acca attc atcgactct agccg a gaaaacg t gta a a ggcttg g g a a gctt t gatt ctc t gctggcagct g gttgcattgaaccattagt cgtggtttcaagca ctgcaattttactactag g g g aaaaatg tctatacactgagcctg tacacggcgtgatg ctg tcaaggtcccctcg g g aacagctaatgagtactgatctagtataaataagatctcaag gacag acccgt tcaggaacatatttcag gttgacaacg g attacg gaaacaagt caattgtgttg tctaaacta g a g ctg gctgttag acgtctg acgaccacgat cctgtttctcatctt aa a gcatgctatta ttttgca caggtttt tagt a ca g gta ccacg gctcg t gat ga caag g gttttttagcgaaat cgtt aaacttccttcgtttacgattg gatagaaattgctgccttaagcata gtaccttgtc tg t g t g gtctgtgccg gtact cg gacg g gta a cagc c agaaaga catt taaactg ct acc agtctgttgtt cgactcta aagctc cg g g gctaattact ttcaggaacatgtgt gctc atttgtg tatcttttatctatg gtg g g ga ctctttccagtttaacttcgtg54gt aga caggacg attgtgtt cccgtctagtcgtcatgttaactttttttat cg g cttagttcaccg cttct ctc ccttgtaatg a g cg atact cgg0tattg gcgat ag0c tttgttctgc cc ggagtagagcc cg gttg g gtgaaag tcgtgacaatttgt ccggaagttttc gtc tgtaaggttc tt a- gct a9tctagttgacccagtttc aagtt cta ct aatgca acag gataatctttg gt aacc gaaagcaaaa tct ac ggtatttgcctgttatccggc gag cgtg g g gtttatgtgcg gatat aatattt ctgtgc aaaactatg ctttttttgtc ata ggtc cgcaacgactctct acaccaagtcg6 g47accgcttccgttataccaagtagg gggtatgtgtccga acttgctga agaatc cgaactttgacgttggttcactctctgtaagctgcagtc1g0aggat ctcgaaattg ttgacaaacaagaac at attgata tt tg ctgtaatg ga cttgtactgacg gaagtcaagt ctagt tcg t g ggagt gtg g2gaaaataag c ggtgctatctga atacaatg gccagtacgaaaagagttt cttaagatct atttcttgtg cctct cgtc g ctcacgag g gcta:.aocgagacaatgg ggtgctacacataagactgatttttg gtgga cgatagagacgcaaaa aacgcgacaggcgaaattgagga aggtccgaacc cgctgtacctttcttgat cttgtttctcggatttctttcattg g gcccc actaaatgtcgtcctg gtcNtekco 1Dvy9e1nr86ott08 A 21gggctg a t gtagtgc atccgaagtaatccc c c gaaacccggta catc g t cac cgtg cc aca ttcctcatta g c c aaagtccctac c ggtgactaag ct aa tat a aataccacattgatctgaatga c cagcag atggcg g acctgcttttcggt cgtaatg atgtaatttaagtgg ctggccttcctaatg cccaaccaacgcttccaag atg ggtgtg ggtacagctgatactatcgaacgtg g atacaaaaacacgtcag g aacaaaacagaccgcaacg ggtgtg ttactagcaagtacattgcgtgctaatg gtttgcgactattcg gacaagg cagacc ag a gtg g gtt ccc aat ct tga ctacccgacggacagcg ag ttgtttgggcacggtatattcat cc cttgtttagctacggactgg gtcg ggaacacag gtgg ttgctaacaaaagc tgaatcaacagtcacgcttcacgaactgaaaggaagctgtggtctgatacg g gctgaagcactcctcg cc acaggcgaccgagcccacccttatagttt ag atag gtcactatcgacgtaag ggcg g gatttctacggcgacc caaac ac agccttaaagct gcg aag g gt gca aa attgtta tagacacg ga c5taaatacaaatgcatgcgaataagtacgtgc aaccgctccatg atccatcgga cccccccctaaatcagaaaag g atgtgtaagggaaagaga40a0cttttgg g ccttc-ttggtgag ggtccccca cg ggactgctgttctgattcttatt ccctctg g g atccac tg gtatagcttacctaggcagagg gccgcaaact tagaacagatcggtgcctaaccgtcgagaacgcctctttagt agtccttt aaaaac at atggtccctaagag gaacaa9 g 6ctggcg 4t7cact ta ctctttcttagatagtg t gacatgttgttatatcaagag gtcgaagaggcc cctg gag gcaacac catta agaac cccacta ggc tggattct ctaaa c tg1gagga g gt aggat atgcgtaccg g cgtgctaaccttaccgtgac ggaatgt gtgtg gatgaacttgta agcgt0g2a cgccttcatccgttc a aagtg ggggtgagtga acatctcg ga caccagtt gcga agcaccacattagccaatttcaatttgtg gggt:.tgcaa aagtgatttatg ggccgaatcttcctcaagtgtt cgccgttaacca cg gtcccgt agct c acctgacgttggaggtga a tgactaatgatg at atc ga tc g aG att ttgtacaccgac g gctgctgtcacatatc ta cgat cc tgatcgt ctgacatcataa ac a agaca ag gataaoa ctt cga a a cgtgt ctt c a a cgtg g ga cg gcga c c cgcagcctctgtagcgtNtekc7o 45 1Dvye-i91nr- M 86o VttR AR _T 08 A E 1 L 21gac a gccaa c g c g c gtaaa ccgcgttatcggtgct cat a atatcgttgaagca cccggacag a c g catgcttg a ata gat gtttgttt gcc g ct c aca cc ccc c gtt t c tgt t cta agg gtatactccaag caacttccgctcctagacaaatcttccgtatag ctatg g gagcgtcaattcttgcacg gaagtaacacgagctag atg cagtcatcgaatcg tagagaacacatggaacagcacaaactaatag ataaggaaaagccaccacccaaccgacacccacccgt tcaggtg g g g g g gcgatag ggtgttacagtggtag atacgctcgtcg acacc ccaacct acatgtggtga cctgagcagcg cagt aca c ccac gcatatccccgactt cacgctgt ataatccttcactgtacactcaccag g g g gccatg acta tccccg aaaaagt tgatgacagaaacctacctattgcg gtg agtca acctg atac ag g gacaagagagattatcaaatcatgttgt cgatacgtgccgtgcaatacat aag g gctg gac a cgacctccattc cgatt ccta aaacatagtgaggtgt tgaagggtgcgaga acgatcctct atgcagtaaag gtg gtc cg gg54aataag atag aatttgc gacgt agggg cttataaccgagacagag g gcgaagaacgtattg tccacgaggatcga cacctcacccgcgaag gcc a aggtcttctgtgag gttagaacg g ccttcgcatgt tccag0a cgac atgacagacg g ggt ac ggcgtgcgt gattgaga cga cccg0-tt9g gagtcgaaacggtcgccgcgcc ccagtttatatgta cacttgggctacgc aa gtt cgta cgcttaccacaccaggcgtgtcgctc cat6a4aagttcgtgtactggataaagttgctgag ggatgtcacc7ca tc tttagcaatga cggtgtcgagaccacgagtccgagcggtaatcgcgtg g c1tga tccttcatc gaaaagtattaacaaccgt c catg ga g cttaac ccacac cgttatg gaagttcacgaggatagaga cgg g gat c cgca0g2tg gt a cg c gattcacacggacaatacccctgac ctaaactacagc ctacatacgttgataagtgagagagagta atagccgtg ccccc ag:.aaaagaccttg gat cattgtaccgatc ag g gtccccaaaatcttaactccagacctgaaaggcta cctttttcacgagtgtacatgcgcacoaattggtggt cgacgtggattggacggaagattcgtagtataa agcccatgagctggt aattagctttagtgtctagcacgaagacactattagcacccgctagtgagatccgtg tcgtcg g ggactg gccgcgNtekc8o 45 1Dvye- 9nry1 s C p_ 8 - R 6otty C2irT 0 G 8 A 6 C L 21g c g c a g a ggcg ttctcac c ctctagt agg ggta c ccc t cc g ctg g tg cac tcagaccagcactgt a cttgcaagagctgg gttgc caag ga cgtacacga c ct g cgt ccgtgaaat atg gcgatctacgcgcgacttagcaagcaggcccg cac ag gggtacgcgtcg ctgcgtgcgccccggtg g ccgcgacaattgcgctaag gctg ctccacgtgatcgct cgcgcgagcg gcatgcgg acacgccccgccgtcgcaacagg gccagctccag cctccgccttcagag g c ggtacg gcttcg c g cgtg acacg g g gcacccctg agggat gcta tgctgattg gcgcctaacatgc g gcgatctac aacc cgcccacc cg gttagtgg c gattcatag gcttgt cgg aagcaagcg g caag ctccg ctgctagagcatg ggtg gagctcgcgact a cg gc tatcatc gccatatcaatc tgactctaccgag gg gcccg ctaccattgaacgc gacgtttg ctaccacctcacg g gtccaagccct atagcggaggcgac atctattgagct gc attaccccc c agc5 gg4 gag g ggg gac ca ccc aa g c g ggctg gcg a g ggccag gcgt cctg catggcgcgactgctaatcaagtgccgtgaactac cagcacgacggcacgccaga actcgcaat caccacc catcgtcgc0g ct ag gttactagccaggccaagggag g ca0c-tcagtctg gccg gctgccg ta cgcgccatat a aggcgcacaggtgtacg gac gcagt cg g ct9ctt c tttccg gtcacctggccg cagagctaccgcgaca ga cc cc cga a aattg g g gagtcccaaggtaatagagaga cg gtc6c gcc agtccag cc atcgc atg aa agcactgtggcggcagcga cagcgccg cc cgccca agcagtaaag ccaac cggatcg gtcgtg47gccag gaatgag g ca ccccaatcgcc g act acgcga gc c aatgcaagtgcgtcatgc agtagcgctagtcttaa agatgaa ca agccc1 g gc0c2cccct gaag ccgcacata tcaacctgtgtc cc g cc acg gccgcaagt ta ctagccttt acgccagcta actgtttgaggtgtaaagtcctccggagcggtcttg g g ggtacct cgacg ctacg g ccct ag g ct ctgcaaggagggccaggagaacg c g ccag tctaccgcg g:.acgagg tatagtg gacacaaatcgctcc cgtg gatg acgacctag gaatttcacacgcgcatg gggcattt ag gccaagattc ag gocg gct caagcggacagcgaacgaaacgag ggagcgagag gccaagtg g ggcctgcgtg gcagtaNtekco 1Dvy9e1nr86ott08 A 21gcgttat c c cgca cacgctc cata t gtaagctat g g g g tgg t a cact a cccattctca gggaa cgc cccatggcaaccgtg ggccg tt c cat acgccca cg g g g ggcacctgactaggag g a g gtg agcctcgctttttaccgcgacacatttcgcatcagtagtct gacg cacagcgtctggaaagg gcg tcccaacagcctcgg g caacg g g g gttctg ggacg caccaatagcgccagcccacg g ctgttcccgacttg gttccttatg ccg ggccaccg gcacggtccg gttag acg catacacgcgag gat gccagtcc tactg gccacgg attg g gcgcgcgg ctgtctccgcgtgacc tttcctcatgag g ggccag gcgtcgccccagccctag atc ctcgcgtac cg gccg g ggaggtgt ac cggcggcg g c g g gcgc cataccgcgcccgaatcggctgtgcattggcgt ccgctatatttggcttcagc cttcatcg g gaaggc cgtcacgcgatgtt gc ctg gggccctc c caagcg gtc cacgcgcaggc agctgc c cgaaaagcgtgca cgccgtaagtgcgagcaaggccgggctatcacacacgagataaggcagccg atggcgtgttgcgcg g g gg ggcacgctggac cggc cgccga gcttgttacgcgcccagccgactagtgctag actg g g cgtct cgatgcgcg g g gggcc c a cgtacg ggag ggtccgaggcg ggcgag gccg ggctg ctt c cc5gccaatatgcctc gcctgta gcc tctc cccctgcgcgcg gtgttgc c c4agtgtctt c gag tctt cgtc0tagc gct tcgc acttcg gctc acgtatgcgctacg0- ggcctgccgcca ag gcgcg g cc ag tattagctg ccatg gtg acag gcggc ctga ttc g g cc ag ctcat ttacgttaa agaaatgcggctgcg 9ca ccc atcgctacca aacccacaagcaaacgtc cgagtg cc tc agtg gaga cggcgg cttac cgacgctg g gccgatacag gacgctgttg6ctctcag g g g g ggacctg g ggcgcgc gag gc gagc caaacgcggcgcgaaaag cgccatcctctcctgagatag g gcttcac ct aagc cg ggcgcg4 g 7a1cgtagtc gt gta g c gtc t cg g gcccggccta cctcgaacctccttg ctg cca gccttgtgt cctggccgcgctgcgaataatttgcgtttctg0ctg c2 gaca cctc a acaa...

Claims

1. Attorney Docket No.: 2017469-0045 CLAIMS 1. A template RNA comprising: a 5’ long terminal repeat (5’ LTR) having a sequence according to column 3 of Table G, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; a 3’ long terminal repeat (3’ LTR) having a sequence according to column 5 of the same row of Table G as the 5’ LTR, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; a heterologous object sequence encoding a therapeutic effector, positioned between the 5’ LTR and the 3’ LTR; and a primer binding site (PBS).

2. A system for modifying DNA comprising: a) a template RNA of claim 1, or a DNA molecule encoding the template RNA; and b) a polypeptide driver having an amino acid sequence according to Table B that corresponds to the 5’ LTR and 3’ LTR, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; or a nucleic acid molecule or a plurality of nucleic acid molecules encoding the polypeptide driver.

3. The system of claim 2, wherein the polypeptide driver further comprises an amino acid sequence according to Table C that corresponds to the 5’ LTR and 3’ LTR, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto.

4. The system of claim 3, wherein the polypeptide driver further comprises an amino acid sequence according to Table D that corresponds to the 5’ LTR and 3’ LTR, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto.

5. The system of claim 4, wherein the polypeptide driver further comprises an amino acid sequence according to Table E that corresponds to the 5’ LTR and 3’ LTR, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. Page 352 of 356 12806819v1 Attorney Docket No.: 2017469-0045 6. The system of claim 5, wherein the polypeptide driver further comprises an amino acid sequence according to Table F that corresponds to the 5’ LTR and 3’ LTR, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto.

7. A polypeptide driver having an amino acid sequence according to Table B, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto.

8. A nucleic acid molecule or a plurality of nucleic acid molecules (e.g., mRNA) encoding the polypeptide driver of claim 7.

9. A template RNA comprising: a 5’ long terminal repeat (5’ LTR) having a sequence according to column 3 of Table J, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; a 3’ long terminal repeat (3’ LTR) having a sequence according to column 5 of the same row of Table J as the 5’ LTR, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; a heterologous object sequence encoding a therapeutic effector, positioned between the 5’ LTR and the 3’ LTR, and a primer binding site (PBS).

10. A system for modifying DNA comprising: a) a template RNA of claim 9, or a DNA molecule encoding the template RNA; and b) a polypeptide driver having an amino acid sequence according to Table L that corresponds to the 5’ LTR and 3’ LTR, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; or a nucleic acid molecule or a plurality of nucleic acid molecules encoding the polypeptide driver.

11. The system of claim 10, wherein the polypeptide driver further comprises an amino acid sequence according to Table M that corresponds to the 5’ LTR and 3’ LTR, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. Page 353 of 356 12806819v1 Attorney Docket No.: 2017469-0045 12. The system of claim 11, wherein the polypeptide driver further comprises an amino acid sequence according to Table N that corresponds to the 5’ LTR and 3’ LTR, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto.

13. The system of claim 12, wherein the polypeptide driver further comprises an amino acid sequence according to Table O that corresponds to the 5’ LTR and 3’ LTR, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto.

14. The system of claim 13, wherein the polypeptide driver further comprises an amino acid sequence according to Table P that corresponds to the 5’ LTR and 3’ LTR, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto.

15. A polypeptide driver having an amino acid sequence according to Table L, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto.

16. A nucleic acid molecule or a plurality of nucleic acid molecules (e.g., mRNA) encoding the polypeptide driver of claim 15.

17. A DNA molecule encoding the template RNA of any one of the preceding claims.

18. A pharmaceutical composition comprising the template RNA or the system of any one of the preceding claims.

19. The system, polypeptide driver, or method of any preceding claim, wherein the system, nucleic acid molecule, polypeptide, and / or DNA encoding the same, is formulated as a lipid nanoparticle (LNP).

20. A cell comprising the system of any one of the preceding claims.

21. A cell comprising the template RNA of any one of the preceding claims. Page 354 of 356 12806819v1 Attorney Docket No.: 2017469-0045 22. A cell comprising the polypeptide driver of any one of the preceding claims.

23. A method of delivering a heterologous object sequence to a target cell, comprising: introducing into the target cell (e.g., contacting the target cell with) a system of any one of the preceding claims, and incubating the target cell under conditions suitable for production of the template DNA. Page 355 of 356 12806819v1