45f1a3e54be3483bffe6ec12b976797f pmc_10138841.pdf 7bda869be25d18cef65dd726b0c828e7520a08ee pmc_10138841.pdf 4a747d6abf6336fde8b8a5e61091ece0b42cf09d0a0bb9da32cc41e237908745 pmc_10138841.pdf Title: Epstein-Barr Virus and Multiple Sclerosis: A Convoluted Interaction and the Opportunity to Unravel Predictive Biomarkers Subject: Since the early 1980s, Epstein-Barr virus (EBV) infection has been described as one of the main risk factors for developing multiple sclerosis (MS), and recently, new epidemiological evidence has reinforced this premise. EBV seroconversion precedes almost 99% of the new cases of MS and likely predates the first clinical symptoms. The molecular mechanisms of this association are complex and may involve different immunological routes, perhaps all running in parallel (i.e., molecular mimicry, the bystander damage theory, abnormal cytokine networks, and coinfection of EBV with retroviruses, among others). However, despite the large amount of evidence available on these topics, the ultimate role of EBV in the pathogenesis of MS is not fully understood. For instance, it is unclear why after EBV infection some individuals develop MS while others evolve to lymphoproliferative disorders or systemic autoimmune diseases. In this regard, recent studies suggest that the virus may exert epigenetic control over MS susceptibility genes by means of specific virulence factors. Such genetic manipulation has been described in virally-infected memory B cells from patients with MS and are thought to be the main source of autoreactive immune responses. Yet, the role of EBV infection in the natural history of MS and in the initiation of neurodegeneration is even less clear. In this narrative review, we will discuss the available evidence on these topics and the possibility of harnessing such immunological alterations to uncover predictive biomarkers for the onset of MS and perhaps facilitate prognostication of the clinical course. Keywords: acute infectious mononucleosis; B cells; chronic EBV infection; Epstein Barr-Virus; EBV latency programs; genomic studies; immune response; molecular mimicry; multiple sclerosis; predictive biomarkers; serum neurofilament light chain protein Author: Oscar-Danilo Ortega-Hernandez, Eva M. Martínez-Cáceres, Silvia Presas-Rodríguez and Cristina Ramo-Tello Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Tue Apr 18 04:59:33 2023 CEST ModDate: Tue Apr 18 05:02:16 2023 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 18 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1752181 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- MXTWPO+VnURWPalladioL Type 1 Custom yes yes no 10 0 XTREYI+URWPalladioL-Bold Type 1 Custom yes yes no 15 0 FZTIHC+URWPalladioL-Roma Type 1 Custom yes yes no 20 0 EVFXCD+URWPalladioL-Ital Type 1 Custom yes yes no 24 0 SSNIUI+VnURWPalladioL-Bold Type 1 Custom yes yes no 28 0 IRWHZX+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 46 0 CKUPDE+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 49 0 APFDOF+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 78 0 APFDPH+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 81 0 APFDPJ+PalatinoLinotype TrueType WinAnsi yes yes no 84 0 BCDEEE+PalatinoLinotype-Bold TrueType WinAnsi yes yes no 99 0 BCDFEE+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 103 0 BCDGEE+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 107 0 ArialMT TrueType WinAnsi no no no 111 0 BCDEEE+PalatinoLinotype-Bold TrueType WinAnsi yes yes no 135 0 BCDFEE+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 139 0 BCDGEE+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 143 0 LWLIVD+EURM10 Type 1 Builtin yes yes no 164 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-09-02 02:28:03 CEST RepresentationInformation: pmc_10138841.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-07-27 02:24:21 CEST Size: 1752181 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 517 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Item: Title: Overview of the Pathophysiology of EBV Infection Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Item: Title: EBV and the Risk for MS: Evidence from Genomic Studies Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Children: Item: Title: Regulation of MS Susceptibility Genes by EBV-Transcriptional Factors Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Genomic Control of EBNA2 in Other Chronic Inflammatory Diseases Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: EBV-microRNAs in the Pathogenesis of MS and Cancer Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: EBV Decides the Fate of Infected B Cells and Likely of Autoreactive B Cells Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Children: Item: Title: The Role of Other EBV-Encoding Products in the Pathogenesis of MS Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: EBV and Autoreactive B Cells in MS Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: Where Does EBV Actually Reside in Patients with MS? Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: EBV Infection and the Chance of Discovering Predictive Biomarkers for MS Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Children: Item: Title: EBV and Neurodegeneration in MS Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: EBV Vaccination and Anti-CD20 Therapies Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Info: Title: Epstein-Barr Virus and Multiple Sclerosis: A Convoluted Interaction and the Opportunity to Unravel Predictive Biomarkers Author: Oscar-Danilo Ortega-Hernandez, Eva M. Martínez-Cáceres, Silvia Presas-Rodríguez and Cristina Ramo-Tello Subject: Since the early 1980s, Epstein-Barr virus (EBV) infection has been described as one of the main risk factors for developing multiple sclerosis (MS), and recently, new epidemiological evidence has reinforced this premise. EBV seroconversion precedes almost 99% of the new cases of MS and likely predates the first clinical symptoms. The molecular mechanisms of this association are complex and may involve different immunological routes, perhaps all running in parallel (i.e., molecular mimicry, the bystander damage theory, abnormal cytokine networks, and coinfection of EBV with retroviruses, among others). However, despite the large amount of evidence available on these topics, the ultimate role of EBV in the pathogenesis of MS is not fully understood. For instance, it is unclear why after EBV infection some individuals develop MS while others evolve to lymphoproliferative disorders or systemic autoimmune diseases. In this regard, recent studies suggest that the virus may exert epigenetic control over MS susceptibility genes by means of specific virulence factors. Such genetic manipulation has been described in virally-infected memory B cells from patients with MS and are thought to be the main source of autoreactive immune responses. Yet, the role of EBV infection in the natural history of MS and in the initiation of neurodegeneration is even less clear. In this narrative review, we will discuss the available evidence on these topics and the possibility of harnessing such immunological alterations to uncover predictive biomarkers for the onset of MS and perhaps facilitate prognostication of the clinical course. Keywords: acute infectious mononucleosis; B cells; chronic EBV infection; Epstein Barr-Virus; EBV latency programs; genomic studies; immune response; molecular mimicry; multiple sclerosis; predictive biomarkers; serum neurofilament light chain protein Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Tue Apr 18 04:59:33 CEST 2023 ModDate: Tue Apr 18 05:02:16 CEST 2023 ID: 0x6d1f00bd07b69e4fb469b850e301299b, 0x6d1f00bd07b69e4fb469b850e301299b Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: FZTIHC+URWPalladioL-Roma FontSubset: true FirstChar: 2 LastChar: 252 FontDescriptor: FontName: FZTIHC+URWPalladioL-Roma Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: LWLIVD+EURM10 FontSubset: true FirstChar: 12 LastChar: 12 FontDescriptor: FontName: LWLIVD+EURM10 Flags: Symbolic FontBBox: -32, -243, 1060, 720 FontFile: true Font: BaseFont: EVFXCD+URWPalladioL-Ital FontSubset: true FirstChar: 3 LastChar: 121 FontDescriptor: FontName: EVFXCD+URWPalladioL-Ital Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: MXTWPO+VnURWPalladioL FontSubset: true FirstChar: 161 LastChar: 225 FontDescriptor: FontName: MXTWPO+VnURWPalladioL Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: SSNIUI+VnURWPalladioL-Bold FontSubset: true FirstChar: 161 LastChar: 189 FontDescriptor: FontName: SSNIUI+VnURWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: XTREYI+URWPalladioL-Bold FontSubset: true FirstChar: 3 LastChar: 122 FontDescriptor: FontName: XTREYI+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Pages: Page: Sequence: 1 Annotations: Annotation: Subtype: Link Rect: 82, 281, 152, 290 Annotation: Subtype: Link Rect: 34, 269, 103, 278 Annotation: Subtype: Link Rect: 34, 164, 96, 186 Annotation: Subtype: Link Rect: 126, 90, 154, 99 Annotation: Subtype: Link Rect: 34, 78, 147, 87 Annotation: Subtype: Link Rect: 34, 756, 180, 792 Annotation: Subtype: Link Rect: 515, 756, 560, 792 Annotation: Subtype: Link Rect: 189, 644, 200, 657 Annotation: Subtype: Link Rect: 330, 644, 341, 657 Annotation: Subtype: Link Rect: 152, 633, 163, 645 Annotation: Subtype: Link Rect: 474, 183, 481, 192 ActionDest: 161 Annotation: Subtype: Link Rect: 482, 183, 489, 192 ActionDest: 161 Annotation: Subtype: Link Rect: 340, 158, 346, 167 ActionDest: 161 Annotation: Subtype: Link Rect: 350, 158, 357, 167 ActionDest: 161 Annotation: Subtype: Link Rect: 249, 145, 256, 154 ActionDest: 161 Annotation: Subtype: Link Rect: 309, 120, 316, 129 ActionDest: 161 Annotation: Subtype: Link Rect: 379, 108, 386, 117 ActionDest: 161 Annotation: Subtype: Link Rect: 193, 82, 200, 91 ActionDest: 161 Annotation: Subtype: Link Rect: 497, 70, 504, 79 ActionDest: 161 Annotation: Subtype: Link Rect: 139, 17, 278, 28 Annotation: Subtype: Link Rect: 422, 17, 560, 28 Annotation: Subtype: Link Rect: 34, 378, 87, 397 Page: Sequence: 2 Annotations: Annotation: Subtype: Link Rect: 233, 720, 240, 732 ActionDest: 68 Annotation: Subtype: Link Rect: 247, 723, 259, 732 ActionDest: 161 Annotation: Subtype: Link Rect: 262, 723, 274, 732 ActionDest: 161 Annotation: Subtype: Link Rect: 480, 280, 487, 289 ActionDest: 161 Annotation: Subtype: Link Rect: 354, 254, 366, 264 ActionDest: 161 Annotation: Subtype: Link Rect: 369, 254, 381, 264 ActionDest: 161 Annotation: Subtype: Link Rect: 491, 229, 503, 238 ActionDest: 168 Annotation: Subtype: Link Rect: 506, 229, 518, 238 ActionDest: 168 Annotation: Subtype: Link Rect: 297, 192, 309, 201 ActionDest: 168 Annotation: Subtype: Link Rect: 312, 192, 324, 201 ActionDest: 168 Annotation: Subtype: Link Rect: 325, 179, 337, 188 ActionDest: 168 Annotation: Subtype: Link Rect: 340, 179, 352, 188 ActionDest: 168 Annotation: Subtype: Link Rect: 237, 129, 249, 138 ActionDest: 168 Annotation: Subtype: Link Rect: 250, 129, 262, 138 ActionDest: 168 Annotation: Subtype: Link Rect: 544, 116, 556, 125 ActionDest: 168 Annotation: Subtype: Link Rect: 495, 79, 507, 88 ActionDest: 168 Page: Sequence: 3 Annotations: Annotation: Subtype: Link Rect: 412, 723, 424, 732 ActionDest: 168 Annotation: Subtype: Link Rect: 425, 723, 437, 732 ActionDest: 168 Annotation: Subtype: Link Rect: 366, 698, 378, 707 ActionDest: 168 Annotation: Subtype: Link Rect: 327, 660, 338, 669 ActionDest: 168 Annotation: Subtype: Link Rect: 339, 660, 351, 669 ActionDest: 168 Annotation: Subtype: Link Rect: 363, 597, 370, 606 ActionDest: 161 Annotation: Subtype: Link Rect: 243, 559, 255, 568 ActionDest: 168 Annotation: Subtype: Link Rect: 293, 534, 305, 543 ActionDest: 168 Annotation: Subtype: Link Rect: 184, 472, 196, 481 ActionDest: 168 Annotation: Subtype: Link Rect: 209, 434, 221, 443 ActionDest: 168 Annotation: Subtype: Link Rect: 222, 434, 234, 443 ActionDest: 171 Annotation: Subtype: Link Rect: 200, 383, 212, 392 ActionDest: 168 Annotation: Subtype: Link Rect: 212, 383, 224, 392 ActionDest: 171 Annotation: Subtype: Link Rect: 429, 371, 441, 380 ActionDest: 171 Annotation: Subtype: Link Rect: 441, 371, 453, 380 ActionDest: 171 Annotation: Subtype: Link Rect: 501, 358, 513, 367 ActionDest: 168 Annotation: Subtype: Link Rect: 455, 333, 467, 342 ActionDest: 171 Annotation: Subtype: Link Rect: 347, 308, 359, 317 ActionDest: 171 Annotation: Subtype: Link Rect: 353, 283, 365, 292 ActionDest: 171 Annotation: Subtype: Link Rect: 239, 258, 251, 267 ActionDest: 171 Annotation: Subtype: Link Rect: 199, 230, 206, 242 ActionDest: 91 Annotation: Subtype: Link Rect: 213, 233, 225, 242 ActionDest: 171 Annotation: Subtype: Link Rect: 495, 170, 507, 179 ActionDest: 171 Annotation: Subtype: Link Rect: 297, 142, 304, 154 ActionDest: 115 Annotation: Subtype: Link Rect: 311, 145, 323, 154 ActionDest: 171 Annotation: Subtype: Link Rect: 197, 69, 209, 79 ActionDest: 171 Annotation: Subtype: Link Rect: 209, 69, 221, 79 ActionDest: 171 Page: Sequence: 4 Page: Sequence: 5 Annotations: Annotation: Subtype: Link Rect: 764, 424, 775, 433 ActionDest: 168 Annotation: Subtype: Link Rect: 764, 368, 775, 376 ActionDest: 171 Annotation: Subtype: Link Rect: 753, 295, 764, 304 ActionDest: 171 Annotation: Subtype: Link Rect: 764, 295, 775, 304 ActionDest: 171 Annotation: Subtype: Link Rect: 776, 295, 787, 304 ActionDest: 171 Annotation: Subtype: Link Rect: 748, 184, 758, 193 ActionDest: 171 Annotation: Subtype: Link Rect: 759, 184, 770, 193 ActionDest: 171 Annotation: Subtype: Link Rect: 770, 184, 781, 193 ActionDest: 171 Annotation: Subtype: Link Rect: 781, 184, 792, 193 ActionDest: 171 Page: Sequence: 6 Annotations: Annotation: Subtype: Link Rect: 260, 690, 272, 699 ActionDest: 171 Annotation: Subtype: Link Rect: 453, 678, 465, 687 ActionDest: 171 Annotation: Subtype: Link Rect: 465, 678, 477, 687 ActionDest: 171 Annotation: Subtype: Link Rect: 480, 678, 492, 687 ActionDest: 171 Annotation: Subtype: Link Rect: 386, 602, 398, 611 ActionDest: 171 Annotation: Subtype: Link Rect: 358, 527, 370, 536 ActionDest: 171 Annotation: Subtype: Link Rect: 304, 499, 311, 511 ActionDest: 91 Annotation: Subtype: Link Rect: 425, 476, 437, 486 ActionDest: 171 Annotation: Subtype: Link Rect: 437, 476, 449, 486 ActionDest: 171 Annotation: Subtype: Link Rect: 330, 426, 342, 435 ActionDest: 171 Annotation: Subtype: Link Rect: 365, 414, 377, 423 ActionDest: 171 Annotation: Subtype: Link Rect: 248, 338, 260, 347 ActionDest: 171 Annotation: Subtype: Link Rect: 260, 338, 272, 347 ActionDest: 171 Annotation: Subtype: Link Rect: 263, 313, 275, 322 ActionDest: 171 Annotation: Subtype: Link Rect: 276, 313, 288, 322 ActionDest: 171 Annotation: Subtype: Link Rect: 431, 212, 443, 221 ActionDest: 171 Annotation: Subtype: Link Rect: 443, 212, 455, 221 ActionDest: 171 Annotation: Subtype: Link Rect: 335, 200, 347, 209 ActionDest: 171 Annotation: Subtype: Link Rect: 215, 124, 226, 133 ActionDest: 171 Annotation: Subtype: Link Rect: 433, 112, 445, 121 ActionDest: 171 Annotation: Subtype: Link Rect: 386, 74, 398, 83 ActionDest: 171 Annotation: Subtype: Link Rect: 398, 74, 410, 83 ActionDest: 171 Page: Sequence: 7 Annotations: Annotation: Subtype: Link Rect: 209, 725, 221, 734 ActionDest: 171 Annotation: Subtype: Link Rect: 235, 675, 247, 684 ActionDest: 168 Annotation: Subtype: Link Rect: 248, 675, 260, 684 ActionDest: 171 Annotation: Subtype: Link Rect: 281, 624, 293, 633 ActionDest: 174 Annotation: Subtype: Link Rect: 219, 599, 231, 608 ActionDest: 168 Annotation: Subtype: Link Rect: 276, 536, 288, 545 ActionDest: 174 Annotation: Subtype: Link Rect: 237, 499, 249, 508 ActionDest: 174 Annotation: Subtype: Link Rect: 201, 473, 213, 483 ActionDest: 171 Annotation: Subtype: Link Rect: 390, 408, 397, 420 ActionDest: 115 Annotation: Subtype: Link Rect: 404, 411, 416, 420 ActionDest: 171 Annotation: Subtype: Link Rect: 417, 411, 429, 420 ActionDest: 174 Annotation: Subtype: Link Rect: 462, 335, 474, 344 ActionDest: 171 Annotation: Subtype: Link Rect: 199, 310, 211, 319 ActionDest: 174 Annotation: Subtype: Link Rect: 454, 310, 466, 319 ActionDest: 171 Annotation: Subtype: Link Rect: 345, 285, 357, 294 ActionDest: 174 Annotation: Subtype: Link Rect: 208, 234, 220, 243 ActionDest: 174 Annotation: Subtype: Link Rect: 342, 209, 354, 218 ActionDest: 168 Annotation: Subtype: Link Rect: 438, 197, 450, 206 ActionDest: 174 Annotation: Subtype: Link Rect: 462, 134, 473, 143 ActionDest: 174 Annotation: Subtype: Link Rect: 474, 134, 486, 143 ActionDest: 174 Annotation: Subtype: Link Rect: 519, 121, 531, 130 ActionDest: 168 Annotation: Subtype: Link Rect: 531, 121, 543, 130 ActionDest: 171 Annotation: Subtype: Link Rect: 544, 122, 556, 130 ActionDest: 174 Page: Sequence: 8 Annotations: Annotation: Subtype: Link Rect: 270, 737, 282, 746 ActionDest: 168 Annotation: Subtype: Link Rect: 282, 737, 294, 746 ActionDest: 174 Annotation: Subtype: Link Rect: 295, 725, 307, 734 ActionDest: 174 Annotation: Subtype: Link Rect: 514, 712, 526, 721 ActionDest: 174 Annotation: Subtype: Link Rect: 338, 675, 350, 684 ActionDest: 174 Annotation: Subtype: Link Rect: 185, 624, 197, 633 ActionDest: 174 Annotation: Subtype: Link Rect: 197, 599, 209, 608 ActionDest: 168 Annotation: Subtype: Link Rect: 209, 599, 221, 608 ActionDest: 174 Annotation: Subtype: Link Rect: 448, 572, 455, 584 ActionDest: 127 Annotation: Subtype: Link Rect: 462, 574, 474, 583 ActionDest: 174 Page: Sequence: 9 Page: Sequence: 10 Page: Sequence: 11 Annotations: Annotation: Subtype: Link Rect: 368, 690, 379, 699 ActionDest: 174 Annotation: Subtype: Link Rect: 380, 690, 392, 699 ActionDest: 174 Annotation: Subtype: Link Rect: 283, 652, 295, 662 ActionDest: 174 Annotation: Subtype: Link Rect: 296, 652, 308, 662 ActionDest: 174 Annotation: Subtype: Link Rect: 532, 615, 544, 624 ActionDest: 174 Annotation: Subtype: Link Rect: 544, 615, 556, 624 ActionDest: 174 Annotation: Subtype: Link Rect: 505, 602, 517, 611 ActionDest: 174 Annotation: Subtype: Link Rect: 517, 602, 529, 611 ActionDest: 174 Annotation: Subtype: Link Rect: 183, 539, 195, 549 ActionDest: 174 Annotation: Subtype: Link Rect: 544, 527, 556, 536 ActionDest: 174 Annotation: Subtype: Link Rect: 376, 489, 388, 498 ActionDest: 174 Annotation: Subtype: Link Rect: 391, 489, 403, 498 ActionDest: 177 Annotation: Subtype: Link Rect: 295, 462, 302, 474 ActionDest: 127 Annotation: Subtype: Link Rect: 309, 464, 321, 473 ActionDest: 177 Annotation: Subtype: Link Rect: 284, 376, 296, 385 ActionDest: 177 Annotation: Subtype: Link Rect: 297, 376, 309, 385 ActionDest: 177 Annotation: Subtype: Link Rect: 423, 338, 429, 347 ActionDest: 161 Annotation: Subtype: Link Rect: 430, 339, 442, 347 ActionDest: 168 Annotation: Subtype: Link Rect: 307, 301, 318, 310 ActionDest: 171 Annotation: Subtype: Link Rect: 213, 276, 225, 285 ActionDest: 177 Annotation: Subtype: Link Rect: 259, 200, 271, 209 ActionDest: 177 Annotation: Subtype: Link Rect: 331, 187, 343, 197 ActionDest: 177 Annotation: Subtype: Link Rect: 531, 162, 543, 171 ActionDest: 177 Annotation: Subtype: Link Rect: 544, 162, 556, 171 ActionDest: 177 Annotation: Subtype: Link Rect: 458, 137, 475, 146 ActionDest: 177 Annotation: Subtype: Link Rect: 475, 137, 492, 146 ActionDest: 177 Annotation: Subtype: Link Rect: 309, 112, 326, 121 ActionDest: 177 Annotation: Subtype: Link Rect: 290, 75, 297, 84 ActionDest: 161 Annotation: Subtype: Link Rect: 297, 74, 314, 84 ActionDest: 177 Page: Sequence: 12 Annotations: Annotation: Subtype: Link Rect: 236, 725, 243, 734 ActionDest: 161 Annotation: Subtype: Link Rect: 438, 712, 455, 721 ActionDest: 177 Annotation: Subtype: Link Rect: 372, 687, 389, 696 ActionDest: 177 Annotation: Subtype: Link Rect: 390, 687, 407, 696 ActionDest: 177 Annotation: Subtype: Link Rect: 350, 549, 367, 558 ActionDest: 177 Annotation: Subtype: Link Rect: 367, 549, 384, 558 ActionDest: 177 Annotation: Subtype: Link Rect: 365, 524, 382, 533 ActionDest: 177 Annotation: Subtype: Link Rect: 502, 486, 519, 495 ActionDest: 177 Page: Sequence: 13 Page: Sequence: 14 Annotations: Annotation: Subtype: Link Rect: 131, 453, 168, 463 Annotation: Subtype: Link Rect: 175, 453, 211, 463 Annotation: Subtype: Link Rect: 99, 418, 137, 428 Annotation: Subtype: Link Rect: 143, 418, 179, 428 Annotation: Subtype: Link Rect: 519, 394, 557, 405 Annotation: Subtype: Link Rect: 59, 384, 95, 394 Annotation: Subtype: Link Rect: 279, 360, 317, 371 Annotation: Subtype: Link Rect: 417, 337, 454, 348 Annotation: Subtype: Link Rect: 374, 302, 411, 313 Annotation: Subtype: Link Rect: 59, 269, 96, 279 Annotation: Subtype: Link Rect: 390, 245, 427, 256 Annotation: Subtype: Link Rect: 415, 222, 452, 233 Annotation: Subtype: Link Rect: 372, 199, 409, 210 Annotation: Subtype: Link Rect: 261, 164, 298, 175 Annotation: Subtype: Link Rect: 304, 164, 340, 175 Annotation: Subtype: Link Rect: 477, 141, 514, 152 Annotation: Subtype: Link Rect: 521, 141, 557, 152 Annotation: Subtype: Link Rect: 341, 118, 378, 129 Annotation: Subtype: Link Rect: 384, 118, 420, 129 Annotation: Subtype: Link Rect: 257, 95, 294, 106 Annotation: Subtype: Link Rect: 301, 95, 337, 106 Annotation: Subtype: Link Rect: 171, 72, 209, 83 Page: Sequence: 15 Annotations: Annotation: Subtype: Link Rect: 520, 701, 557, 712 Annotation: Subtype: Link Rect: 484, 689, 522, 700 Annotation: Subtype: Link Rect: 504, 666, 541, 677 Annotation: Subtype: Link Rect: 144, 632, 182, 642 Annotation: Subtype: Link Rect: 140, 598, 177, 608 Annotation: Subtype: Link Rect: 184, 598, 220, 608 Annotation: Subtype: Link Rect: 144, 563, 182, 573 Annotation: Subtype: Link Rect: 188, 563, 224, 573 Annotation: Subtype: Link Rect: 380, 539, 417, 550 Annotation: Subtype: Link Rect: 423, 539, 459, 550 Annotation: Subtype: Link Rect: 220, 506, 257, 516 Annotation: Subtype: Link Rect: 471, 482, 508, 493 Annotation: Subtype: Link Rect: 108, 460, 146, 470 Annotation: Subtype: Link Rect: 59, 425, 96, 435 Annotation: Subtype: Link Rect: 230, 401, 267, 412 Annotation: Subtype: Link Rect: 520, 378, 557, 389 Annotation: Subtype: Link Rect: 153, 345, 191, 355 Annotation: Subtype: Link Rect: 59, 322, 96, 332 Annotation: Subtype: Link Rect: 102, 322, 138, 332 Annotation: Subtype: Link Rect: 453, 298, 490, 309 Annotation: Subtype: Link Rect: 496, 298, 532, 309 Annotation: Subtype: Link Rect: 131, 253, 168, 263 Annotation: Subtype: Link Rect: 175, 253, 211, 263 Annotation: Subtype: Link Rect: 489, 229, 527, 240 Annotation: Subtype: Link Rect: 476, 194, 560, 205 Annotation: Subtype: Link Rect: 56, 183, 177, 194 Annotation: Subtype: Link Rect: 316, 148, 520, 159 Annotation: Subtype: Link Rect: 494, 114, 532, 125 Annotation: Subtype: Link Rect: 235, 80, 273, 90 Page: Sequence: 16 Annotations: Annotation: Subtype: Link Rect: 506, 724, 544, 735 Annotation: Subtype: Link Rect: 500, 701, 538, 712 Annotation: Subtype: Link Rect: 59, 678, 96, 689 Annotation: Subtype: Link Rect: 59, 655, 96, 665 Annotation: Subtype: Link Rect: 102, 655, 138, 665 Annotation: Subtype: Link Rect: 174, 632, 211, 642 Annotation: Subtype: Link Rect: 217, 632, 253, 642 Annotation: Subtype: Link Rect: 255, 597, 293, 608 Annotation: Subtype: Link Rect: 299, 597, 335, 608 Annotation: Subtype: Link Rect: 388, 585, 426, 596 Annotation: Subtype: Link Rect: 174, 563, 211, 573 Annotation: Subtype: Link Rect: 300, 528, 338, 539 Annotation: Subtype: Link Rect: 483, 516, 520, 527 Annotation: Subtype: Link Rect: 59, 483, 96, 493 Annotation: Subtype: Link Rect: 215, 448, 252, 458 Annotation: Subtype: Link Rect: 419, 424, 456, 435 Annotation: Subtype: Link Rect: 462, 424, 498, 435 Annotation: Subtype: Link Rect: 158, 391, 195, 401 Annotation: Subtype: Link Rect: 201, 391, 237, 401 Annotation: Subtype: Link Rect: 59, 356, 96, 366 Annotation: Subtype: Link Rect: 102, 356, 138, 366 Annotation: Subtype: Link Rect: 276, 332, 314, 343 Annotation: Subtype: Link Rect: 320, 332, 356, 343 Annotation: Subtype: Link Rect: 59, 287, 96, 297 Annotation: Subtype: Link Rect: 439, 263, 477, 274 Annotation: Subtype: Link Rect: 505, 252, 542, 263 Annotation: Subtype: Link Rect: 234, 229, 271, 240 Annotation: Subtype: Link Rect: 151, 207, 189, 217 Annotation: Subtype: Link Rect: 178, 184, 216, 194 Annotation: Subtype: Link Rect: 222, 184, 258, 194 Annotation: Subtype: Link Rect: 349, 148, 386, 159 Annotation: Subtype: Link Rect: 393, 148, 429, 159 Annotation: Subtype: Link Rect: 238, 126, 276, 136 Annotation: Subtype: Link Rect: 301, 102, 338, 113 Annotation: Subtype: Link Rect: 344, 102, 380, 113 Annotation: Subtype: Link Rect: 131, 69, 168, 79 Annotation: Subtype: Link Rect: 175, 69, 211, 79 Page: Sequence: 17 Annotations: Annotation: Subtype: Link Rect: 316, 724, 354, 735 Annotation: Subtype: Link Rect: 104, 690, 142, 700 Annotation: Subtype: Link Rect: 113, 655, 150, 665 Annotation: Subtype: Link Rect: 109, 621, 146, 631 Annotation: Subtype: Link Rect: 426, 597, 464, 608 Annotation: Subtype: Link Rect: 59, 575, 96, 585 Annotation: Subtype: Link Rect: 102, 575, 138, 585 Annotation: Subtype: Link Rect: 59, 552, 96, 562 Annotation: Subtype: Link Rect: 102, 552, 138, 562 Annotation: Subtype: Link Rect: 245, 517, 283, 527 Annotation: Subtype: Link Rect: 289, 517, 325, 527 Annotation: Subtype: Link Rect: 130, 483, 168, 493 Annotation: Subtype: Link Rect: 174, 483, 210, 493 Annotation: Subtype: Link Rect: 519, 459, 557, 470 Annotation: Subtype: Link Rect: 59, 448, 95, 458 Annotation: Subtype: Link Rect: 289, 424, 327, 435 Annotation: Subtype: Link Rect: 333, 424, 369, 435 Annotation: Subtype: Link Rect: 265, 401, 303, 412 Annotation: Subtype: Link Rect: 108, 379, 146, 389 Annotation: Subtype: Link Rect: 421, 355, 458, 366 Annotation: Subtype: Link Rect: 369, 332, 560, 343 Annotation: Subtype: Link Rect: 59, 287, 96, 297 Annotation: Subtype: Link Rect: 109, 264, 146, 274 Annotation: Subtype: Link Rect: 152, 264, 188, 274 Annotation: Subtype: Link Rect: 264, 240, 301, 251 Annotation: Subtype: Link Rect: 307, 240, 343, 251 Annotation: Subtype: Link Rect: 446, 217, 483, 228 Annotation: Subtype: Link Rect: 489, 217, 525, 228 Annotation: Subtype: Link Rect: 214, 194, 251, 205 Annotation: Subtype: Link Rect: 257, 194, 293, 205 Annotation: Subtype: Link Rect: 508, 171, 546, 182 Annotation: Subtype: Link Rect: 318, 148, 356, 159 Annotation: Subtype: Link Rect: 418, 125, 456, 136 Annotation: Subtype: Link Rect: 425, 91, 463, 102 Annotation: Subtype: Link Rect: 127, 69, 164, 79 Page: Sequence: 18 Annotations: Annotation: Subtype: Link Rect: 445, 724, 483, 735 Annotation: Subtype: Link Rect: 59, 690, 96, 700 Annotation: Subtype: Link Rect: 102, 690, 138, 700 Annotation: Subtype: Link Rect: 95, 667, 132, 677 Annotation: Subtype: Link Rect: 139, 667, 175, 677 Annotation: Subtype: Link Rect: 59, 644, 96, 654 Annotation: Subtype: Link Rect: 102, 644, 138, 654 Annotation: Subtype: Link Rect: 316, 620, 354, 631 Annotation: Subtype: Link Rect: 360, 620, 396, 631 Annotation: Subtype: Link Rect: 117, 598, 155, 608 Annotation: Subtype: Link Rect: 104, 575, 141, 585 Annotation: Subtype: Link Rect: 237, 552, 275, 562 Annotation: Subtype: Link Rect: 501, 528, 539, 539 Annotation: Subtype: Link Rect: 500, 505, 538, 516 Annotation: Subtype: Link Rect: 514, 482, 551, 493 Annotation: Subtype: Link Rect: 59, 448, 96, 458 Annotation: Subtype: Link Rect: 102, 448, 138, 458 Annotation: Subtype: Link Rect: 59, 414, 96, 424 Annotation: Subtype: Link Rect: 102, 414, 138, 424 Annotation: Subtype: Link Rect: 376, 379, 413, 389 Annotation: Subtype: Link Rect: 420, 379, 456, 389 Annotation: Subtype: Link Rect: 297, 344, 506, 355 Annotation: Subtype: Link Rect: 444, 309, 560, 320 Annotation: Subtype: Link Rect: 56, 298, 144, 309 Annotation: Subtype: Link Rect: 400, 275, 438, 286 Annotation: Subtype: Link Rect: 444, 275, 480, 286 Annotation: Subtype: Link Rect: 59, 241, 96, 251 Checksum: cdee822e Type: CRC32 Checksum: 45f1a3e54be3483bffe6ec12b976797f Type: MD5 Checksum: 7bda869be25d18cef65dd726b0c828e7520a08ee Type: SHA-1