b4e43f636c963047005c11b3b7d840e5 pmc_32973882.pdf e3897df39a6eba43343c223d92e7f4f2076ae46b pmc_32973882.pdf e48aa4aa98cce4278435f58448124301b9b8e439b550b0d91af5afab00b01b26 pmc_32973882.pdf Title: High-Throughput Sequencing to Investigate Associations Between HLA Genes and Metamizole-Induced Agranulocytosis Subject: Background and objective: Agranulocytosis is a rare and potentially life-threatening complication of metamizole (dipyrone) intake that is characterized by a loss of circulating neutrophil granulocytes. Keywords: drug-induced agranulocytosis, metamizole (dipyrone), HLA, pharmacogenetics, high-throughput sequencing, next generation sequencing, genetic association studies Author: Ursula Amstutz Creator: LaTeX with hyperref package Producer: pdfTeX-1.40.15 CreationDate: Thu Aug 20 16:34:47 2020 CEST ModDate: Thu Aug 20 17:19:38 2020 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 15 Encrypted: no Page size: 595.276 x 779.528 pts Page rot: 0 File size: 2145099 bytes Optimized: no PDF version: 1.6 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- VIFWOO+MinionPro-Regular Type 1 Custom yes yes no 32 0 JNWRPV+HelveticaNeueLTStd-Bd Type 1 Custom yes yes no 33 0 PIFPRC+HelveticaNeueLTStd-Lt Type 1 Custom yes yes no 34 0 CDEMIC+HelveticaNeueLTStd-BdIt Type 1 Custom yes yes no 39 0 MKDDNZ+HelveticaNeueLTStd-LtIt Type 1 Custom yes yes no 40 0 ZJUCSG+HelveticaNeueLTStd-MdIt Type 1 Custom yes yes no 41 0 ZCTSWW+MTSYN Type 1 Builtin yes yes no 151 0 XODHDR+RBLMI Type 1 Builtin yes yes no 150 0 FSAJUU+MinionPro-It Type 1 Custom yes yes no 156 0 ONAWGD+MinionPro-Bold Type 1 Custom yes yes no 232 0 JYDOCF+MTGU Type 1 Builtin yes yes no 233 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2020-11-18 06:05:28 CET RepresentationInformation: pmc_32973882.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2020-09-28 03:35:17 CEST Size: 2145099 Format: PDF Version: 1.6 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 0 FreeObjects: 5 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseOutlines Outlines: Item: Title: High-Throughput Sequencing to Investigate Associations Between HLA Genes and Metamizole-Induced Agranulocytosis Children: Item: Title: Introduction Item: Title: Materials and Methods Children: Item: Title: Participants and Setting Item: Title: DNA and Template Preparation Item: Title: Multiplex Library Preparation and Sequencing of the Discovery Subset Item: Title: Quality Control and HLA Typing of the Discovery Subset Item: Title: Genotyping Using Genome-Wide SNP Arrays Item: Title: Imputation of SNPs and HLA Types From Genome-Wide SNP Array Data Item: Title: Investigation of Individual Variants in Classical HLA Class I Genes From HTS Data in the Discovery Subset Item: Title: Statistical Analysis Item: Title: Results Children: Item: Title: Participants Item: Title: Sequencing and HTS-Based Typing of the Discovery Subset Item: Title: Association Analyses and Identification of Candidate Alleles in the Discovery Subset Item: Title: Replication of Candidate Associations Using HLA Imputation Item: Title: Associations of Individual Sequence Variants in Full-Length Genes Item: Title: Discovery Meta-Analysis of Imputed HLA Alleles Across Cohorts Item: Title: Discussion Children: Item: Title: Metamizole-Induced Agranulocytosis and HLA Gene Variation Item: Title: HTS-Based HLA Sequencing for Pharmacogenetic Association Studies Item: Title: Conclusion Item: Title: EuDac Collaborative Authors Item: Title: Data Availability Statement Item: Title: Ethics Statement Item: Title: Author Contributions Item: Title: Funding Item: Title: Acknowledgments Item: Title: Supplementary Material Item: Title: References Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: VIFWOO+MinionPro-Regular FontSubset: true FirstChar: 1 LastChar: 252 FontDescriptor: FontName: VIFWOO+MinionPro-Regular Flags: Symbolic FontBBox: -289, -360, 1684, 917 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: JNWRPV+HelveticaNeueLTStd-Bd FontSubset: true FirstChar: 2 LastChar: 124 FontDescriptor: FontName: JNWRPV+HelveticaNeueLTStd-Bd Flags: Symbolic FontBBox: -166, -218, 1078, 975 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: PIFPRC+HelveticaNeueLTStd-Lt FontSubset: true FirstChar: 2 LastChar: 150 FontDescriptor: FontName: PIFPRC+HelveticaNeueLTStd-Lt Flags: Symbolic FontBBox: -166, -214, 1050, 967 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: XODHDR+RBLMI FontSubset: true FirstChar: 60 LastChar: 62 FontDescriptor: FontName: XODHDR+RBLMI Flags: Symbolic FontBBox: -11, -230, 987, 750 FontFile: true Font: BaseFont: CDEMIC+HelveticaNeueLTStd-BdIt FontSubset: true FirstChar: 42 LastChar: 121 FontDescriptor: FontName: CDEMIC+HelveticaNeueLTStd-BdIt Flags: Symbolic FontBBox: -166, -218, 1129, 975 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: ZCTSWW+MTSYN FontSubset: true FirstChar: 0 LastChar: 110 FontDescriptor: FontName: ZCTSWW+MTSYN Flags: Symbolic FontBBox: 0, -954, 1043, 900 FontFile: true Font: BaseFont: MKDDNZ+HelveticaNeueLTStd-LtIt FontSubset: true FirstChar: 2 LastChar: 252 FontDescriptor: FontName: MKDDNZ+HelveticaNeueLTStd-LtIt Flags: Symbolic FontBBox: -165, -214, 1099, 951 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: ONAWGD+MinionPro-Bold FontSubset: true FirstChar: 3 LastChar: 121 FontDescriptor: FontName: ONAWGD+MinionPro-Bold Flags: Symbolic FontBBox: -318, -360, 1684, 917 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: ZJUCSG+HelveticaNeueLTStd-MdIt FontSubset: true FirstChar: 42 LastChar: 241 FontDescriptor: FontName: ZJUCSG+HelveticaNeueLTStd-MdIt Flags: Symbolic FontBBox: -165, -218, 1125, 947 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: JYDOCF+MTGU FontSubset: true FirstChar: 109 LastChar: 109 FontDescriptor: FontName: JYDOCF+MTGU Flags: Symbolic FontBBox: 25, -213, 839, 683 FontFile: true Font: BaseFont: FSAJUU+MinionPro-It FontSubset: true FirstChar: 40 LastChar: 241 FontDescriptor: FontName: FSAJUU+MinionPro-It Flags: Symbolic FontBBox: -201, -360, 1684, 919 FontFile: true EncodingDictionary: Differences: true XMP: drug-induced agranulocytosis, metamizole (dipyrone), HLA, pharmacogenetics, high-throughput sequencing, next generation sequencing, genetic association studies pdfTeX-1.40.15 1.5 application/pdf fgene-11-00951.tex High-Throughput Sequencing to Investigate Associations Between HLA Genes and Metamizole-Induced Agranulocytosis Background and objective: Agranulocytosis is a rare and potentially life-threatening complication of metamizole (dipyrone) intake that is characterized by a loss of circulating neutrophil granulocytes. Ursula Amstutz drug-induced agranulocytosis metamizole (dipyrone) HLA pharmacogenetics high-throughput sequencing next generation sequencing genetic association studies 2020-08-20T20:04:47+05:30 2020-08-20T20:04:47+05:30 2020-08-20T20:49:38+05:30 2020-08-20T20:49:38+05:30 LaTeX with hyperref package uuid:6759590a-8dc9-45fd-9dce-467f7f7541d1 uuid:6ba6ee65-6c09-443e-9f13-747113114db2 Pages: Page: Sequence: 1 Annotations: Annotation: Subtype: Link Rect: 43, 718, 133, 754 Annotation: Subtype: Link Rect: 474, 736, 551, 745 Annotation: Subtype: Link Rect: 467, 727, 551, 737 Annotation: Subtype: Link Rect: 453, 718, 551, 729 Annotation: Subtype: Link Rect: 86, 495, 160, 505 Annotation: Subtype: Link Rect: 75, 65, 160, 74 Annotation: Subtype: Link Rect: 521, 677, 551, 707 Annotation: Subtype: Link Rect: 176, 521, 551, 611 Annotation: Subtype: Link Rect: 176, 500, 266, 510 Annotation: Subtype: Link Rect: 280, 500, 332, 510 Annotation: Subtype: Link Rect: 341, 500, 406, 510 Annotation: Subtype: Link Rect: 176, 489, 250, 499 Annotation: Subtype: Link Rect: 176, 478, 233, 488 Annotation: Subtype: Link Rect: 337, 478, 408, 488 Annotation: Subtype: Link Rect: 419, 478, 497, 488 Annotation: Subtype: Link Rect: 176, 467, 241, 479 Annotation: Subtype: Link Rect: 43, 29, 107, 38 Annotation: Subtype: Link Rect: 111, 29, 171, 38 Annotation: Subtype: Link Rect: 435, 29, 551, 38 Page: Sequence: 2 Annotations: Annotation: Subtype: Link Rect: 137, 465, 183, 477 ActionDest: 714 Annotation: Subtype: Link Rect: 188, 465, 208, 477 ActionDest: 714 Annotation: Subtype: Link Rect: 96, 443, 185, 454 ActionDest: 644 Annotation: Subtype: Link Rect: 188, 443, 208, 454 ActionDest: 644 Annotation: Subtype: Link Rect: 211, 443, 267, 454 ActionDest: 644 Annotation: Subtype: Link Rect: 270, 443, 290, 454 ActionDest: 644 Annotation: Subtype: Link Rect: 43, 431, 99, 442 ActionDest: 771 Annotation: Subtype: Link Rect: 103, 431, 123, 442 ActionDest: 771 Annotation: Subtype: Link Rect: 127, 431, 175, 442 ActionDest: 644 Annotation: Subtype: Link Rect: 178, 431, 199, 442 ActionDest: 644 Annotation: Subtype: Link Rect: 208, 397, 260, 408 ActionDest: 644 Annotation: Subtype: Link Rect: 267, 397, 287, 408 ActionDest: 644 Annotation: Subtype: Link Rect: 84, 351, 183, 362 ActionDest: 714 Annotation: Subtype: Link Rect: 187, 351, 207, 362 ActionDest: 714 Annotation: Subtype: Link Rect: 211, 351, 262, 362 ActionDest: 714 Annotation: Subtype: Link Rect: 267, 351, 287, 362 ActionDest: 714 Annotation: Subtype: Link Rect: 110, 329, 191, 339 ActionDest: 771 Annotation: Subtype: Link Rect: 194, 329, 215, 339 ActionDest: 771 Annotation: Subtype: Link Rect: 218, 329, 267, 339 ActionDest: 714 Annotation: Subtype: Link Rect: 270, 329, 290, 339 ActionDest: 714 Annotation: Subtype: Link Rect: 43, 317, 89, 328 ActionDest: 644 Annotation: Subtype: Link Rect: 92, 317, 113, 328 ActionDest: 644 Annotation: Subtype: Link Rect: 47, 259, 112, 270 ActionDest: 714 Annotation: Subtype: Link Rect: 116, 259, 136, 270 ActionDest: 714 Annotation: Subtype: Link Rect: 140, 259, 239, 270 ActionDest: 714 Annotation: Subtype: Link Rect: 243, 259, 263, 270 ActionDest: 714 Annotation: Subtype: Link Rect: 267, 259, 292, 270 ActionDest: 644 Annotation: Subtype: Link Rect: 43, 248, 63, 259 ActionDest: 644 Annotation: Subtype: Link Rect: 66, 248, 86, 259 ActionDest: 644 Annotation: Subtype: Link Rect: 88, 248, 164, 259 ActionDest: 771 Annotation: Subtype: Link Rect: 167, 248, 187, 259 ActionDest: 771 Annotation: Subtype: Link Rect: 189, 248, 248, 259 ActionDest: 771 Annotation: Subtype: Link Rect: 250, 248, 270, 259 ActionDest: 771 Annotation: Subtype: Link Rect: 200, 156, 223, 167 ActionDest: 714 Annotation: Subtype: Link Rect: 229, 156, 249, 167 ActionDest: 714 Annotation: Subtype: Link Rect: 255, 156, 290, 167 ActionDest: 771 Annotation: Subtype: Link Rect: 43, 145, 64, 156 ActionDest: 771 Annotation: Subtype: Link Rect: 68, 145, 156, 156 ActionDest: 714 Annotation: Subtype: Link Rect: 159, 145, 180, 156 ActionDest: 714 Annotation: Subtype: Link Rect: 183, 145, 236, 156 ActionDest: 644 Annotation: Subtype: Link Rect: 240, 145, 260, 156 ActionDest: 644 Annotation: Subtype: Link Rect: 208, 110, 262, 121 ActionDest: 771 Annotation: Subtype: Link Rect: 267, 110, 287, 121 ActionDest: 771 Annotation: Subtype: Link Rect: 412, 501, 471, 512 ActionDest: 714 Annotation: Subtype: Link Rect: 475, 501, 496, 512 ActionDest: 714 Annotation: Subtype: Link Rect: 500, 501, 549, 512 ActionDest: 714 Annotation: Subtype: Link Rect: 302, 490, 322, 501 ActionDest: 714 Annotation: Subtype: Link Rect: 324, 490, 381, 501 ActionDest: 771 Annotation: Subtype: Link Rect: 383, 490, 403, 501 ActionDest: 771 Annotation: Subtype: Link Rect: 521, 467, 551, 478 ActionDest: 714 Annotation: Subtype: Link Rect: 302, 455, 325, 466 ActionDest: 714 Annotation: Subtype: Link Rect: 330, 455, 350, 466 ActionDest: 714 Annotation: Subtype: Link Rect: 374, 409, 395, 421 ActionDest: 771 Annotation: Subtype: Link Rect: 397, 409, 417, 421 ActionDest: 771 Annotation: Subtype: Link Rect: 473, 318, 524, 329 ActionDest: 771 Annotation: Subtype: Link Rect: 528, 318, 549, 329 ActionDest: 771 Annotation: Subtype: Link Rect: 302, 307, 361, 318 ActionDest: 771 Annotation: Subtype: Link Rect: 363, 307, 383, 318 ActionDest: 771 Annotation: Subtype: Link Rect: 334, 260, 384, 272 ActionDest: 771 Annotation: Subtype: Link Rect: 389, 260, 409, 272 ActionDest: 771 Annotation: Subtype: Link Rect: 413, 260, 487, 272 ActionDest: 771 Annotation: Subtype: Link Rect: 492, 260, 512, 272 ActionDest: 771 Annotation: Subtype: Link Rect: 516, 260, 551, 272 ActionDest: 644 Annotation: Subtype: Link Rect: 302, 249, 323, 260 ActionDest: 644 Annotation: Subtype: Link Rect: 327, 249, 347, 260 ActionDest: 644 Annotation: Subtype: Link Rect: 351, 249, 418, 260 ActionDest: 714 Annotation: Subtype: Link Rect: 422, 249, 442, 260 ActionDest: 714 Annotation: Subtype: Link Rect: 353, 192, 428, 203 ActionDest: 714 Annotation: Subtype: Link Rect: 431, 192, 451, 203 ActionDest: 714 Annotation: Subtype: Link Rect: 305, 134, 356, 146 ActionDest: 771 Annotation: Subtype: Link Rect: 360, 134, 380, 146 ActionDest: 771 Annotation: Subtype: Link Rect: 385, 134, 453, 146 ActionDest: 714 Annotation: Subtype: Link Rect: 458, 134, 478, 146 ActionDest: 714 Annotation: Subtype: Link Rect: 482, 134, 549, 146 ActionDest: 714 Annotation: Subtype: Link Rect: 302, 123, 322, 134 ActionDest: 714 Annotation: Subtype: Link Rect: 493, 111, 549, 123 ActionDest: 771 Annotation: Subtype: Link Rect: 302, 100, 322, 111 ActionDest: 771 Annotation: Subtype: Link Rect: 325, 100, 361, 111 ActionDest: 644 Annotation: Subtype: Link Rect: 364, 100, 384, 111 ActionDest: 644 Annotation: Subtype: Link Rect: 387, 100, 434, 111 ActionDest: 771 Annotation: Subtype: Link Rect: 437, 100, 457, 111 ActionDest: 771 Annotation: Subtype: Link Rect: 460, 100, 526, 111 ActionDest: 714 Annotation: Subtype: Link Rect: 528, 100, 549, 111 ActionDest: 714 Annotation: Subtype: Link Rect: 302, 89, 375, 100 ActionDest: 714 Annotation: Subtype: Link Rect: 377, 89, 397, 100 ActionDest: 714 Annotation: Subtype: Link Rect: 387, 77, 455, 88 ActionDest: 714 Annotation: Subtype: Link Rect: 459, 77, 479, 88 ActionDest: 714 Annotation: Subtype: Link Rect: 483, 77, 549, 88 ActionDest: 714 Annotation: Subtype: Link Rect: 302, 66, 322, 77 ActionDest: 714 Annotation: Subtype: Link Rect: 43, 29, 107, 38 Annotation: Subtype: Link Rect: 111, 29, 171, 38 Annotation: Subtype: Link Rect: 435, 29, 551, 38 Page: Sequence: 3 Annotations: Annotation: Subtype: Link Rect: 86, 683, 126, 694 ActionDest: 714 Annotation: Subtype: Link Rect: 128, 683, 148, 694 ActionDest: 714 Annotation: Subtype: Link Rect: 124, 649, 183, 660 ActionDest: 714 Annotation: Subtype: Link Rect: 187, 649, 207, 660 ActionDest: 714 Annotation: Subtype: Link Rect: 211, 649, 290, 660 ActionDest: 714 Annotation: Subtype: Link Rect: 43, 637, 64, 648 ActionDest: 714 Annotation: Subtype: Link Rect: 232, 545, 290, 557 ActionDest: 714 Annotation: Subtype: Link Rect: 43, 534, 64, 545 ActionDest: 714 Annotation: Subtype: Link Rect: 127, 248, 173, 259 ActionDest: 771 Annotation: Subtype: Link Rect: 175, 248, 200, 259 ActionDest: 771 Annotation: Subtype: Link Rect: 491, 660, 549, 671 ActionDest: 714 Annotation: Subtype: Link Rect: 302, 649, 322, 660 ActionDest: 714 Annotation: Subtype: Link Rect: 305, 488, 360, 500 ActionDest: 714 Annotation: Subtype: Link Rect: 363, 488, 383, 500 ActionDest: 714 Annotation: Subtype: Link Rect: 397, 346, 448, 358 ActionDest: 771 Annotation: Subtype: Link Rect: 453, 346, 474, 358 ActionDest: 771 Annotation: Subtype: Link Rect: 479, 346, 549, 358 ActionDest: 714 Annotation: Subtype: Link Rect: 302, 335, 322, 346 ActionDest: 714 Annotation: Subtype: Link Rect: 326, 335, 389, 346 ActionDest: 714 Annotation: Subtype: Link Rect: 392, 335, 412, 346 ActionDest: 714 Annotation: Subtype: Link Rect: 330, 323, 431, 335 ActionDest: 644 Annotation: Subtype: Link Rect: 351, 266, 448, 277 ActionDest: 644 Annotation: Subtype: Link Rect: 302, 110, 402, 121 ActionDest: 644 Annotation: Subtype: Link Rect: 43, 29, 107, 38 Annotation: Subtype: Link Rect: 111, 29, 171, 38 Annotation: Subtype: Link Rect: 435, 29, 551, 38 Page: Sequence: 4 Annotations: Annotation: Subtype: Link Rect: 106, 416, 111, 427 ActionDest: 289 Annotation: Subtype: Link Rect: 197, 416, 245, 427 ActionDest: 714 Annotation: Subtype: Link Rect: 250, 416, 270, 427 ActionDest: 714 Annotation: Subtype: Link Rect: 230, 404, 292, 415 ActionDest: 644 Annotation: Subtype: Link Rect: 43, 392, 85, 404 ActionDest: 644 Annotation: Subtype: Link Rect: 83, 301, 154, 312 ActionDest: 714 Annotation: Subtype: Link Rect: 159, 301, 179, 312 ActionDest: 714 Annotation: Subtype: Link Rect: 130, 289, 228, 301 ActionDest: 714 Annotation: Subtype: Link Rect: 233, 289, 253, 301 ActionDest: 714 Annotation: Subtype: Link Rect: 229, 278, 290, 289 ActionDest: 771 Annotation: Subtype: Link Rect: 43, 266, 64, 278 ActionDest: 771 Annotation: Subtype: Link Rect: 118, 244, 222, 255 ActionDest: 644 Annotation: Subtype: Link Rect: 251, 198, 292, 209 ActionDest: 714 Annotation: Subtype: Link Rect: 43, 186, 96, 197 ActionDest: 714 Annotation: Subtype: Link Rect: 99, 186, 119, 197 ActionDest: 714 Annotation: Subtype: Link Rect: 94, 175, 144, 186 ActionDest: 714 Annotation: Subtype: Link Rect: 147, 175, 167, 186 ActionDest: 714 Annotation: Subtype: Link Rect: 47, 129, 132, 140 ActionDest: 714 Annotation: Subtype: Link Rect: 138, 129, 158, 140 ActionDest: 714 Annotation: Subtype: Link Rect: 230, 118, 292, 129 ActionDest: 644 Annotation: Subtype: Link Rect: 43, 106, 80, 117 ActionDest: 644 Annotation: Subtype: Link Rect: 47, 74, 231, 86 Annotation: Subtype: Link Rect: 492, 694, 551, 706 ActionDest: 771 Annotation: Subtype: Link Rect: 302, 683, 334, 694 ActionDest: 771 Annotation: Subtype: Link Rect: 338, 683, 358, 694 ActionDest: 771 Annotation: Subtype: Link Rect: 362, 683, 393, 694 ActionDest: 771 Annotation: Subtype: Link Rect: 397, 683, 417, 694 ActionDest: 771 Annotation: Subtype: Link Rect: 412, 437, 462, 449 ActionDest: 771 Annotation: Subtype: Link Rect: 464, 437, 485, 449 ActionDest: 771 Annotation: Subtype: Link Rect: 487, 437, 526, 449 ActionDest: 714 Annotation: Subtype: Link Rect: 528, 437, 549, 449 ActionDest: 714 Annotation: Subtype: Link Rect: 302, 426, 353, 437 ActionDest: 644 Annotation: Subtype: Link Rect: 357, 426, 377, 437 ActionDest: 644 Annotation: Subtype: Link Rect: 392, 414, 441, 426 ActionDest: 771 Annotation: Subtype: Link Rect: 443, 414, 463, 426 ActionDest: 771 Annotation: Subtype: Link Rect: 302, 220, 406, 231 ActionDest: 644 Annotation: Subtype: Link Rect: 386, 157, 430, 169 ActionDest: 714 Annotation: Subtype: Link Rect: 437, 157, 457, 169 ActionDest: 714 Annotation: Subtype: Link Rect: 305, 135, 367, 146 ActionDest: 771 Annotation: Subtype: Link Rect: 369, 135, 389, 146 ActionDest: 771 Annotation: Subtype: Link Rect: 355, 123, 360, 134 ActionDest: 289 Annotation: Subtype: Link Rect: 446, 123, 543, 134 ActionDest: 644 Annotation: Subtype: Link Rect: 428, 89, 481, 100 ActionDest: 771 Annotation: Subtype: Link Rect: 487, 89, 507, 100 ActionDest: 771 Annotation: Subtype: Link Rect: 305, 64, 454, 77 Annotation: Subtype: Link Rect: 43, 29, 107, 38 Annotation: Subtype: Link Rect: 111, 29, 171, 38 Annotation: Subtype: Link Rect: 435, 29, 551, 38 Page: Sequence: 5 Annotations: Annotation: Subtype: Link Rect: 158, 694, 210, 706 ActionDest: 771 Annotation: Subtype: Link Rect: 215, 694, 235, 706 ActionDest: 771 Annotation: Subtype: Link Rect: 187, 484, 244, 496 ActionDest: 714 Annotation: Subtype: Link Rect: 250, 484, 270, 496 ActionDest: 714 Annotation: Subtype: Link Rect: 185, 473, 238, 484 ActionDest: 714 Annotation: Subtype: Link Rect: 242, 473, 262, 484 ActionDest: 714 Annotation: Subtype: Link Rect: 183, 450, 245, 461 ActionDest: 714 Annotation: Subtype: Link Rect: 250, 450, 270, 461 ActionDest: 714 Annotation: Subtype: Link Rect: 109, 439, 141, 450 ActionDest: 714 Annotation: Subtype: Link Rect: 144, 439, 164, 450 ActionDest: 714 Annotation: Subtype: Link Rect: 180, 393, 229, 404 ActionDest: 771 Annotation: Subtype: Link Rect: 231, 393, 252, 404 ActionDest: 771 Annotation: Subtype: Link Rect: 389, 576, 517, 587 ActionDest: 771 Annotation: Subtype: Link Rect: 525, 576, 545, 587 ActionDest: 771 Annotation: Subtype: Link Rect: 379, 416, 493, 427 ActionDest: 771 Annotation: Subtype: Link Rect: 497, 416, 517, 427 ActionDest: 771 Annotation: Subtype: Link Rect: 345, 370, 426, 381 ActionDest: 714 Annotation: Subtype: Link Rect: 429, 370, 449, 381 ActionDest: 714 Annotation: Subtype: Link Rect: 43, 29, 107, 38 Annotation: Subtype: Link Rect: 111, 29, 171, 38 Annotation: Subtype: Link Rect: 435, 29, 551, 38 Page: Sequence: 6 Annotations: Annotation: Subtype: Link Rect: 102, 591, 152, 603 ActionDest: 771 Annotation: Subtype: Link Rect: 156, 591, 176, 603 ActionDest: 771 Annotation: Subtype: Link Rect: 54, 158, 89, 170 ActionDest: 343 Annotation: Subtype: Link Rect: 92, 158, 99, 170 ActionDest: 420 Annotation: Subtype: Link Rect: 339, 442, 374, 454 ActionDest: 379 Annotation: Subtype: Link Rect: 412, 420, 448, 431 ActionDest: 379 Annotation: Subtype: Link Rect: 305, 362, 411, 373 ActionDest: 644 Annotation: Subtype: Link Rect: 305, 316, 408, 328 ActionDest: 644 Annotation: Subtype: Link Rect: 488, 270, 551, 282 ActionDest: 644 Annotation: Subtype: Link Rect: 302, 259, 342, 270 ActionDest: 644 Annotation: Subtype: Link Rect: 305, 236, 406, 247 ActionDest: 644 Annotation: Subtype: Link Rect: 351, 202, 453, 213 ActionDest: 644 Annotation: Subtype: Link Rect: 314, 156, 416, 167 ActionDest: 644 Annotation: Subtype: Link Rect: 43, 29, 107, 38 Annotation: Subtype: Link Rect: 111, 29, 171, 38 Annotation: Subtype: Link Rect: 435, 29, 551, 38 Page: Sequence: 7 Annotations: Annotation: Subtype: Link Rect: 47, 275, 82, 286 ActionDest: 420 Annotation: Subtype: Link Rect: 100, 275, 200, 286 ActionDest: 644 Annotation: Subtype: Link Rect: 142, 263, 178, 274 ActionDest: 420 Annotation: Subtype: Link Rect: 47, 252, 153, 263 ActionDest: 644 Annotation: Subtype: Link Rect: 181, 217, 279, 228 ActionDest: 644 Annotation: Subtype: Link Rect: 71, 144, 102, 156 ActionDest: 452 Annotation: Subtype: Link Rect: 73, 122, 103, 133 ActionDest: 452 Annotation: Subtype: Link Rect: 64, 87, 100, 99 ActionDest: 496 Annotation: Subtype: Link Rect: 305, 361, 341, 372 ActionDest: 452 Annotation: Subtype: Link Rect: 43, 29, 107, 38 Annotation: Subtype: Link Rect: 111, 29, 171, 38 Annotation: Subtype: Link Rect: 435, 29, 551, 38 Page: Sequence: 8 Annotations: Annotation: Subtype: Link Rect: 85, 372, 126, 384 ActionDest: 520 Annotation: Subtype: Link Rect: 113, 327, 151, 338 ActionDest: 452 Annotation: Subtype: Link Rect: 305, 672, 403, 683 ActionDest: 644 Annotation: Subtype: Link Rect: 403, 585, 437, 596 ActionDest: 520 Annotation: Subtype: Link Rect: 305, 430, 404, 441 ActionDest: 644 Annotation: Subtype: Link Rect: 376, 338, 479, 349 ActionDest: 644 Annotation: Subtype: Link Rect: 43, 29, 107, 38 Annotation: Subtype: Link Rect: 111, 29, 171, 38 Annotation: Subtype: Link Rect: 435, 29, 551, 38 Page: Sequence: 9 Annotations: Annotation: Subtype: Link Rect: 205, 257, 292, 268 ActionDest: 644 Annotation: Subtype: Link Rect: 43, 245, 55, 257 ActionDest: 644 Annotation: Subtype: Link Rect: 47, 211, 145, 222 ActionDest: 644 Annotation: Subtype: Link Rect: 474, 144, 525, 156 ActionDest: 771 Annotation: Subtype: Link Rect: 528, 144, 549, 156 ActionDest: 771 Annotation: Subtype: Link Rect: 302, 133, 323, 144 ActionDest: 771 Annotation: Subtype: Link Rect: 328, 133, 348, 144 ActionDest: 771 Annotation: Subtype: Link Rect: 332, 64, 378, 76 ActionDest: 771 Annotation: Subtype: Link Rect: 382, 64, 402, 76 ActionDest: 771 Annotation: Subtype: Link Rect: 405, 64, 453, 76 ActionDest: 714 Annotation: Subtype: Link Rect: 457, 64, 477, 76 ActionDest: 714 Annotation: Subtype: Link Rect: 481, 64, 501, 76 ActionDest: 771 Annotation: Subtype: Link Rect: 504, 64, 549, 76 ActionDest: 714 Annotation: Subtype: Link Rect: 43, 29, 107, 38 Annotation: Subtype: Link Rect: 111, 29, 171, 38 Annotation: Subtype: Link Rect: 435, 29, 551, 38 Page: Sequence: 10 Annotations: Annotation: Subtype: Link Rect: 43, 29, 107, 38 Annotation: Subtype: Link Rect: 111, 29, 171, 38 Annotation: Subtype: Link Rect: 435, 29, 551, 38 Page: Sequence: 11 Annotations: Annotation: Subtype: Link Rect: 43, 706, 64, 717 ActionDest: 714 Annotation: Subtype: Link Rect: 68, 706, 115, 717 ActionDest: 714 Annotation: Subtype: Link Rect: 120, 706, 140, 717 ActionDest: 714 Annotation: Subtype: Link Rect: 145, 706, 199, 717 ActionDest: 714 Annotation: Subtype: Link Rect: 202, 706, 222, 717 ActionDest: 714 Annotation: Subtype: Link Rect: 227, 707, 267, 717 ActionDest: 771 Annotation: Subtype: Link Rect: 270, 707, 290, 717 ActionDest: 771 Annotation: Subtype: Link Rect: 43, 696, 77, 706 ActionDest: 714 Annotation: Subtype: Link Rect: 79, 696, 99, 706 ActionDest: 714 Annotation: Subtype: Link Rect: 102, 695, 145, 706 ActionDest: 771 Annotation: Subtype: Link Rect: 148, 695, 168, 706 ActionDest: 771 Annotation: Subtype: Link Rect: 171, 695, 230, 706 ActionDest: 771 Annotation: Subtype: Link Rect: 233, 695, 253, 706 ActionDest: 771 Annotation: Subtype: Link Rect: 47, 603, 94, 614 ActionDest: 771 Annotation: Subtype: Link Rect: 97, 603, 121, 614 ActionDest: 771 Annotation: Subtype: Link Rect: 121, 603, 128, 614 ActionDest: 771 Annotation: Subtype: Link Rect: 135, 568, 188, 580 ActionDest: 714 Annotation: Subtype: Link Rect: 191, 568, 211, 580 ActionDest: 714 Annotation: Subtype: Link Rect: 207, 545, 262, 557 ActionDest: 771 Annotation: Subtype: Link Rect: 267, 545, 287, 557 ActionDest: 771 Annotation: Subtype: Link Rect: 160, 339, 211, 351 ActionDest: 714 Annotation: Subtype: Link Rect: 213, 339, 234, 351 ActionDest: 714 Annotation: Subtype: Link Rect: 47, 157, 93, 167 ActionDest: 771 Annotation: Subtype: Link Rect: 95, 157, 115, 167 ActionDest: 771 Annotation: Subtype: Link Rect: 118, 157, 188, 167 ActionDest: 771 Annotation: Subtype: Link Rect: 190, 157, 210, 167 ActionDest: 771 Annotation: Subtype: Link Rect: 213, 157, 267, 167 ActionDest: 644 Annotation: Subtype: Link Rect: 270, 157, 290, 167 ActionDest: 644 Annotation: Subtype: Link Rect: 43, 146, 108, 156 ActionDest: 714 Annotation: Subtype: Link Rect: 110, 146, 130, 156 ActionDest: 714 Annotation: Subtype: Link Rect: 144, 64, 192, 76 ActionDest: 714 Annotation: Subtype: Link Rect: 196, 64, 216, 76 ActionDest: 714 Annotation: Subtype: Link Rect: 220, 64, 266, 76 ActionDest: 714 Annotation: Subtype: Link Rect: 270, 64, 290, 76 ActionDest: 714 Annotation: Subtype: Link Rect: 302, 706, 344, 717 ActionDest: 714 Annotation: Subtype: Link Rect: 347, 706, 367, 717 ActionDest: 714 Annotation: Subtype: Link Rect: 474, 694, 549, 706 ActionDest: 771 Annotation: Subtype: Link Rect: 302, 683, 322, 694 ActionDest: 771 Annotation: Subtype: Link Rect: 328, 683, 392, 694 ActionDest: 771 Annotation: Subtype: Link Rect: 398, 683, 418, 694 ActionDest: 771 Annotation: Subtype: Link Rect: 508, 626, 549, 637 ActionDest: 714 Annotation: Subtype: Link Rect: 302, 615, 322, 626 ActionDest: 714 Annotation: Subtype: Link Rect: 325, 615, 382, 626 ActionDest: 714 Annotation: Subtype: Link Rect: 384, 615, 404, 626 ActionDest: 714 Annotation: Subtype: Link Rect: 434, 213, 492, 225 ActionDest: 714 Annotation: Subtype: Link Rect: 495, 213, 516, 225 ActionDest: 714 Annotation: Subtype: Link Rect: 519, 213, 551, 225 ActionDest: 714 Annotation: Subtype: Link Rect: 302, 202, 346, 213 ActionDest: 714 Annotation: Subtype: Link Rect: 348, 202, 369, 213 ActionDest: 714 Annotation: Subtype: Link Rect: 381, 144, 448, 156 ActionDest: 714 Annotation: Subtype: Link Rect: 452, 144, 472, 156 ActionDest: 714 Annotation: Subtype: Link Rect: 458, 87, 520, 99 ActionDest: 771 Annotation: Subtype: Link Rect: 525, 87, 545, 99 ActionDest: 771 Annotation: Subtype: Link Rect: 43, 29, 107, 38 Annotation: Subtype: Link Rect: 111, 29, 171, 38 Annotation: Subtype: Link Rect: 435, 29, 551, 38 Page: Sequence: 12 Annotations: Annotation: Subtype: Link Rect: 240, 545, 290, 557 ActionDest: 714 Annotation: Subtype: Link Rect: 43, 534, 64, 545 ActionDest: 714 Annotation: Subtype: Link Rect: 233, 454, 290, 465 ActionDest: 714 Annotation: Subtype: Link Rect: 43, 443, 64, 454 ActionDest: 714 Annotation: Subtype: Link Rect: 105, 397, 172, 408 ActionDest: 714 Annotation: Subtype: Link Rect: 176, 397, 196, 408 ActionDest: 714 Annotation: Subtype: Link Rect: 200, 397, 265, 408 ActionDest: 714 Annotation: Subtype: Link Rect: 269, 397, 289, 408 ActionDest: 714 Annotation: Subtype: Link Rect: 108, 362, 158, 373 ActionDest: 714 Annotation: Subtype: Link Rect: 165, 362, 185, 373 ActionDest: 714 Annotation: Subtype: Link Rect: 163, 237, 233, 247 ActionDest: 771 Annotation: Subtype: Link Rect: 235, 237, 256, 247 ActionDest: 771 Annotation: Subtype: Link Rect: 47, 110, 111, 121 ActionDest: 714 Annotation: Subtype: Link Rect: 113, 110, 133, 121 ActionDest: 714 Annotation: Subtype: Link Rect: 136, 110, 197, 121 ActionDest: 714 Annotation: Subtype: Link Rect: 200, 110, 220, 121 ActionDest: 714 Annotation: Subtype: Link Rect: 171, 88, 217, 99 ActionDest: 771 Annotation: Subtype: Link Rect: 220, 88, 240, 99 ActionDest: 771 Annotation: Subtype: Link Rect: 389, 671, 460, 683 ActionDest: 714 Annotation: Subtype: Link Rect: 466, 671, 486, 683 ActionDest: 714 Annotation: Subtype: Link Rect: 470, 535, 549, 545 ActionDest: 771 Annotation: Subtype: Link Rect: 302, 523, 322, 534 ActionDest: 771 Annotation: Subtype: Link Rect: 43, 29, 107, 38 Annotation: Subtype: Link Rect: 111, 29, 171, 38 Annotation: Subtype: Link Rect: 435, 29, 551, 38 Page: Sequence: 13 Annotations: Annotation: Subtype: Link Rect: 96, 555, 198, 566 ActionDest: 644 Annotation: Subtype: Link Rect: 355, 252, 551, 263 Annotation: Subtype: Link Rect: 302, 241, 460, 252 Annotation: Subtype: Link Rect: 86, 160, 148, 170 Annotation: Subtype: Link Rect: 73, 132, 161, 141 Annotation: Subtype: Link Rect: 279, 113, 293, 122 Annotation: Subtype: Link Rect: 53, 104, 154, 113 Annotation: Subtype: Link Rect: 251, 75, 293, 85 Annotation: Subtype: Link Rect: 53, 68, 117, 74 Annotation: Subtype: Link Rect: 439, 199, 517, 208 Annotation: Subtype: Link Rect: 367, 171, 465, 179 Annotation: Subtype: Link Rect: 457, 142, 551, 151 Annotation: Subtype: Link Rect: 312, 134, 328, 141 Annotation: Subtype: Link Rect: 389, 104, 480, 113 Annotation: Subtype: Link Rect: 341, 66, 440, 75 Annotation: Subtype: Link Rect: 43, 29, 107, 38 Annotation: Subtype: Link Rect: 111, 29, 171, 38 Annotation: Subtype: Link Rect: 435, 29, 551, 38 Page: Sequence: 14 Annotations: Annotation: Subtype: Link Rect: 53, 678, 137, 687 Annotation: Subtype: Link Rect: 279, 650, 293, 659 Annotation: Subtype: Link Rect: 53, 640, 151, 649 Annotation: Subtype: Link Rect: 82, 602, 193, 612 Annotation: Subtype: Link Rect: 103, 574, 293, 583 Annotation: Subtype: Link Rect: 53, 565, 74, 573 Annotation: Subtype: Link Rect: 108, 528, 190, 536 Annotation: Subtype: Link Rect: 197, 508, 293, 517 Annotation: Subtype: Link Rect: 53, 500, 85, 508 Annotation: Subtype: Link Rect: 211, 470, 272, 479 Annotation: Subtype: Link Rect: 90, 441, 154, 451 Annotation: Subtype: Link Rect: 82, 377, 153, 384 Annotation: Subtype: Link Rect: 142, 348, 230, 356 Annotation: Subtype: Link Rect: 100, 319, 210, 328 Annotation: Subtype: Link Rect: 183, 291, 261, 299 Annotation: Subtype: Link Rect: 203, 253, 293, 261 Annotation: Subtype: Link Rect: 53, 243, 80, 251 Annotation: Subtype: Link Rect: 198, 205, 278, 214 Annotation: Subtype: Link Rect: 204, 186, 293, 195 Annotation: Subtype: Link Rect: 53, 176, 113, 186 Annotation: Subtype: Link Rect: 90, 148, 176, 157 Annotation: Subtype: Link Rect: 193, 111, 293, 119 Annotation: Subtype: Link Rect: 53, 102, 73, 109 Annotation: Subtype: Link Rect: 312, 698, 415, 706 Annotation: Subtype: Link Rect: 341, 669, 441, 678 Annotation: Subtype: Link Rect: 348, 631, 433, 640 Annotation: Subtype: Link Rect: 420, 602, 517, 612 Annotation: Subtype: Link Rect: 312, 565, 405, 574 Annotation: Subtype: Link Rect: 312, 536, 412, 545 Annotation: Subtype: Link Rect: 411, 508, 489, 517 Annotation: Subtype: Link Rect: 392, 480, 471, 489 Annotation: Subtype: Link Rect: 537, 460, 551, 470 Annotation: Subtype: Link Rect: 312, 451, 392, 460 Annotation: Subtype: Link Rect: 509, 422, 551, 432 Annotation: Subtype: Link Rect: 312, 415, 346, 422 Annotation: Subtype: Link Rect: 455, 385, 551, 394 Annotation: Subtype: Link Rect: 312, 377, 328, 384 Annotation: Subtype: Link Rect: 396, 357, 473, 366 Annotation: Subtype: Link Rect: 509, 337, 551, 347 Annotation: Subtype: Link Rect: 312, 329, 373, 336 Annotation: Subtype: Link Rect: 312, 290, 388, 299 Annotation: Subtype: Link Rect: 462, 271, 551, 280 Annotation: Subtype: Link Rect: 312, 262, 335, 271 Annotation: Subtype: Link Rect: 312, 233, 420, 243 Annotation: Subtype: Link Rect: 510, 205, 551, 214 Annotation: Subtype: Link Rect: 312, 197, 343, 204 Annotation: Subtype: Link Rect: 312, 157, 412, 167 Annotation: Subtype: Link Rect: 537, 138, 551, 148 Annotation: Subtype: Link Rect: 312, 129, 409, 138 Annotation: Subtype: Link Rect: 458, 92, 551, 101 Annotation: Subtype: Link Rect: 312, 84, 339, 90 Annotation: Subtype: Link Rect: 43, 29, 107, 38 Annotation: Subtype: Link Rect: 111, 29, 171, 38 Annotation: Subtype: Link Rect: 435, 29, 551, 38 Page: Sequence: 15 Annotations: Annotation: Subtype: Link Rect: 91, 688, 184, 697 Annotation: Subtype: Link Rect: 108, 659, 171, 668 Annotation: Subtype: Link Rect: 279, 631, 293, 640 Annotation: Subtype: Link Rect: 53, 622, 133, 630 Annotation: Subtype: Link Rect: 231, 593, 293, 602 Annotation: Subtype: Link Rect: 53, 585, 90, 592 Annotation: Subtype: Link Rect: 251, 546, 293, 555 Annotation: Subtype: Link Rect: 53, 536, 98, 545 Annotation: Subtype: Link Rect: 80, 489, 184, 498 Annotation: Subtype: Link Rect: 215, 460, 293, 470 Annotation: Subtype: Link Rect: 53, 453, 82, 460 Annotation: Subtype: Link Rect: 184, 423, 246, 432 Annotation: Subtype: Link Rect: 242, 394, 293, 403 Annotation: Subtype: Link Rect: 53, 386, 70, 393 Annotation: Subtype: Link Rect: 279, 347, 293, 356 Annotation: Subtype: Link Rect: 53, 337, 173, 347 Annotation: Subtype: Link Rect: 226, 309, 293, 318 Annotation: Subtype: Link Rect: 53, 301, 70, 308 Annotation: Subtype: Link Rect: 53, 271, 171, 280 Annotation: Subtype: Link Rect: 279, 243, 293, 252 Annotation: Subtype: Link Rect: 53, 234, 137, 242 Annotation: Subtype: Link Rect: 211, 205, 293, 214 Annotation: Subtype: Link Rect: 53, 197, 70, 204 Annotation: Subtype: Link Rect: 53, 157, 149, 167 Annotation: Subtype: Link Rect: 93, 120, 202, 129 Annotation: Subtype: Link Rect: 501, 706, 551, 716 Annotation: Subtype: Link Rect: 312, 699, 361, 706 Annotation: Subtype: Link Rect: 497, 678, 551, 687 Annotation: Subtype: Link Rect: 312, 670, 332, 677 Annotation: Subtype: Link Rect: 334, 640, 405, 649 Annotation: Subtype: Link Rect: 351, 602, 469, 612 Annotation: Subtype: Link Rect: 330, 564, 430, 574 Annotation: Subtype: Link Rect: 312, 528, 395, 536 Annotation: Subtype: Link Rect: 510, 498, 551, 508 Annotation: Subtype: Link Rect: 312, 489, 383, 498 Annotation: Subtype: Link Rect: 364, 470, 488, 479 Annotation: Subtype: Link Rect: 510, 441, 551, 451 Annotation: Subtype: Link Rect: 312, 434, 369, 441 Annotation: Subtype: Link Rect: 395, 403, 522, 413 Annotation: Subtype: Link Rect: 402, 375, 502, 384 Annotation: Subtype: Link Rect: 526, 347, 551, 356 Annotation: Subtype: Link Rect: 312, 337, 353, 346 Annotation: Subtype: Link Rect: 328, 309, 389, 318 Annotation: Subtype: Link Rect: 537, 290, 551, 299 Annotation: Subtype: Link Rect: 312, 281, 407, 290 Annotation: Subtype: Link Rect: 348, 252, 506, 261 Annotation: Subtype: Link Rect: 416, 224, 490, 233 Annotation: Subtype: Link Rect: 491, 148, 517, 157 Annotation: Subtype: Link Rect: 519, 148, 551, 157 Annotation: Subtype: Link Rect: 302, 138, 337, 148 Annotation: Subtype: Link Rect: 338, 138, 361, 148 Annotation: Subtype: Link Rect: 361, 138, 388, 148 Annotation: Subtype: Link Rect: 43, 29, 107, 38 Annotation: Subtype: Link Rect: 111, 29, 171, 38 Annotation: Subtype: Link Rect: 435, 29, 551, 38 Checksum: 8849e345 Type: CRC32 Checksum: b4e43f636c963047005c11b3b7d840e5 Type: MD5 Checksum: e3897df39a6eba43343c223d92e7f4f2076ae46b Type: SHA-1