289ec402cc167270914050eb4b9575b2 pmc_33435363.pdf c6f36dfeb141b023cbc8d1c2df144c4471702671 pmc_33435363.pdf 30ac26af7b0e9046990bff9ddb7b359d4a94368c5946847fb2fa3f14e0ea8811 pmc_33435363.pdf Title: microRNAs as Early Biomarkers of Alzheimer’s Disease: A Synaptic Perspective Subject: Pathogenic processes underlying Alzheimer’s disease (AD) affect synaptic function from initial asymptomatic stages, long time before the onset of cognitive decline and neurodegeneration. Therefore, reliable biomarkers enabling early AD diagnosis and prognosis are needed to maximize the time window for therapeutic interventions. MicroRNAs (miRNAs) have recently emerged as promising cost-effective and non-invasive biomarkers for AD, since they can be readily detected in different biofluids, including cerebrospinal fluid (CSF) and blood. Moreover, a growing body of evidence indicates that miRNAs regulate synaptic homeostasis and plasticity processes, suggesting that they may be involved in early synaptic dysfunction during AD. Here, we review the current literature supporting a role of miRNAs during early synaptic deficits in AD, including recent studies evaluating their potential as AD biomarkers. Besides targeting genes related to A and tau metabolism, several miRNAs also regulate synaptic-related proteins and transcription factors implicated in early synaptic deficits during AD. Furthermore, individual miRNAs and molecular signatures have been found to distinguish between prodromal AD and healthy controls. Overall, these studies highlight the relevance of considering synaptic-related miRNAs as potential biomarkers of early AD stages. However, further validation studies in large cohorts, including longitudinal studies, as well as implementation of standardized protocols, are needed to establish miRNA-based biomarkers as reliable diagnostic and prognostic tools. Keywords: miRNAs; synaptic dysfunction; Alzheimer’s disease; biomarkers Author: Dolores Siedlecki-Wullich, Alfredo J. Miñano-Molina and José Rodríguez-Álvarez Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Thu Jan 21 08:58:48 2021 CET ModDate: Thu Jan 21 09:48:08 2021 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 25 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1269645 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- ULTSPI+VnURWPalladioL-Bold Type 1 Custom yes yes no 10 0 OHKNFJ+VnURWPalladioL Type 1 Custom yes yes no 15 0 QDULQU+EURM10 Type 1 Builtin yes yes no 19 0 DEGLVY+URWPalladioL-Ital Type 1 Custom yes yes no 23 0 RUEXSB+URWPalladioL-Bold Type 1 Custom yes yes no 28 0 JIBGFI+URWPalladioL-Roma Type 1 Custom yes yes no 32 0 PFKOHU+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 40 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 62 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 66 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 70 0 BILMOA+PalatinoLinotype TrueType WinAnsi yes yes no 89 0 VORNGC+CMSY10 Type 1 Builtin yes yes no 102 0 LCOJKO+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 119 0 LCOJMA+PalatinoLinotype TrueType WinAnsi yes yes no 122 0 LCOJMC+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 125 0 CRJHCU+PazoMath-Italic Type 1 Builtin yes yes no 139 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2021-09-11 03:54:04 CEST RepresentationInformation: pmc_33435363.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2021-02-08 03:37:38 CET Size: 1269645 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 827 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: Synaptic Function and Synaptic Alteration in AD Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: miRNAs as Mediators of Synaptic Dysfunction in AD Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Children: Item: Title: Synaptic Role of miRNAs Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: miRNAs and Synaptic Dysfunction in AD Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: Role of miRNAs in A/Tau Mediated Synaptic Dysfunction and Neuroinflammation Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: miRNAs as Biomarkers of AD Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Children: Item: Title: Current Biomarkers for AD Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: Synaptic-Related miRNAs as Early Biomarkers for AD Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: Potential and Limitations of Synaptic-Related miRNAs as Early AD Biomarkers Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: miRNAs as Therapeutic Targets Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Item: Title: Concluding Remarks Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@3aeaafa6 Info: Title: microRNAs as Early Biomarkers of Alzheimer’s Disease: A Synaptic Perspective Author: Dolores Siedlecki-Wullich, Alfredo J. Miñano-Molina and José Rodríguez-Álvarez Subject: Pathogenic processes underlying Alzheimer’s disease (AD) affect synaptic function from initial asymptomatic stages, long time before the onset of cognitive decline and neurodegeneration. Therefore, reliable biomarkers enabling early AD diagnosis and prognosis are needed to maximize the time window for therapeutic interventions. MicroRNAs (miRNAs) have recently emerged as promising cost-effective and non-invasive biomarkers for AD, since they can be readily detected in different biofluids, including cerebrospinal fluid (CSF) and blood. Moreover, a growing body of evidence indicates that miRNAs regulate synaptic homeostasis and plasticity processes, suggesting that they may be involved in early synaptic dysfunction during AD. Here, we review the current literature supporting a role of miRNAs during early synaptic deficits in AD, including recent studies evaluating their potential as AD biomarkers. Besides targeting genes related to A and tau metabolism, several miRNAs also regulate synaptic-related proteins and transcription factors implicated in early synaptic deficits during AD. Furthermore, individual miRNAs and molecular signatures have been found to distinguish between prodromal AD and healthy controls. Overall, these studies highlight the relevance of considering synaptic-related miRNAs as potential biomarkers of early AD stages. However, further validation studies in large cohorts, including longitudinal studies, as well as implementation of standardized protocols, are needed to establish miRNA-based biomarkers as reliable diagnostic and prognostic tools. Keywords: miRNAs; synaptic dysfunction; Alzheimer’s disease; biomarkers Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Thu Jan 21 08:58:48 CET 2021 ModDate: Thu Jan 21 09:48:08 CET 2021 ID: 0x1e1b637a2798f667a3c9020ab56d83df, 0x1e1b637a2798f667a3c9020ab56d83df Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: JIBGFI+URWPalladioL-Roma FontSubset: true FirstChar: 2 LastChar: 252 FontDescriptor: FontName: JIBGFI+URWPalladioL-Roma Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: QDULQU+EURM10 FontSubset: true FirstChar: 11 LastChar: 20 FontDescriptor: FontName: QDULQU+EURM10 Flags: Symbolic FontBBox: -32, -243, 1060, 720 FontFile: true Font: BaseFont: VORNGC+CMSY10 FontSubset: true FirstChar: 34 LastChar: 48 FontDescriptor: FontName: VORNGC+CMSY10 Flags: Symbolic FontBBox: -29, -960, 1116, 775 FontFile: true Font: BaseFont: DEGLVY+URWPalladioL-Ital FontSubset: true FirstChar: 3 LastChar: 122 FontDescriptor: FontName: DEGLVY+URWPalladioL-Ital Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: ULTSPI+VnURWPalladioL-Bold FontSubset: true FirstChar: 129 LastChar: 189 FontDescriptor: FontName: ULTSPI+VnURWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: CRJHCU+PazoMath-Italic FontSubset: true FirstChar: 98 LastChar: 98 FontDescriptor: FontName: CRJHCU+PazoMath-Italic Flags: Symbolic FontBBox: -70, -277, 902, 733 FontFile: true Font: BaseFont: RUEXSB+URWPalladioL-Bold FontSubset: true FirstChar: 2 LastChar: 241 FontDescriptor: FontName: RUEXSB+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: OHKNFJ+VnURWPalladioL FontSubset: true FirstChar: 129 LastChar: 226 FontDescriptor: FontName: OHKNFJ+VnURWPalladioL Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Pages: Page: Sequence: 1 Annotations: Annotation: Subtype: Link Rect: 35, 759, 122, 795 Annotation: Subtype: Link Rect: 515, 759, 560, 795 Annotation: Subtype: Link Rect: 182, 659, 193, 673 Annotation: Subtype: Link Rect: 329, 659, 340, 673 Annotation: Subtype: Link Rect: 51, 313, 154, 322 Annotation: Subtype: Link Rect: 35, 303, 78, 310 Annotation: Subtype: Link Rect: 36, 162, 98, 184 Annotation: Subtype: Link Rect: 123, 89, 154, 98 Annotation: Subtype: Link Rect: 35, 77, 154, 86 Annotation: Subtype: Link Rect: 35, 66, 49, 74 Annotation: Subtype: Link Rect: 541, 220, 548, 229 ActionDest: 165 Annotation: Subtype: Link Rect: 549, 220, 556, 229 ActionDest: 165 Annotation: Subtype: Link Rect: 508, 192, 515, 204 ActionDest: 79 Annotation: Subtype: Link Rect: 503, 145, 510, 154 ActionDest: 165 Annotation: Subtype: Link Rect: 527, 132, 534, 141 ActionDest: 165 Annotation: Subtype: Link Rect: 254, 107, 261, 116 ActionDest: 165 Annotation: Subtype: Link Rect: 100, 17, 240, 28 Annotation: Subtype: Link Rect: 419, 17, 558, 28 Annotation: Subtype: Link Rect: 35, 389, 87, 408 Page: Sequence: 2 Annotations: Annotation: Subtype: Link Rect: 371, 711, 378, 721 ActionDest: 165 Annotation: Subtype: Link Rect: 379, 712, 386, 721 ActionDest: 168 Annotation: Subtype: Link Rect: 225, 686, 232, 695 ActionDest: 168 Annotation: Subtype: Link Rect: 238, 674, 245, 683 ActionDest: 165 Annotation: Subtype: Link Rect: 226, 649, 233, 658 ActionDest: 165 Annotation: Subtype: Link Rect: 273, 624, 280, 633 ActionDest: 168 Annotation: Subtype: Link Rect: 280, 624, 287, 633 ActionDest: 168 Annotation: Subtype: Link Rect: 245, 586, 252, 595 ActionDest: 165 Annotation: Subtype: Link Rect: 253, 586, 260, 595 ActionDest: 168 Annotation: Subtype: Link Rect: 213, 573, 220, 582 ActionDest: 165 Annotation: Subtype: Link Rect: 220, 573, 227, 582 ActionDest: 168 Annotation: Subtype: Link Rect: 234, 548, 246, 557 ActionDest: 168 Annotation: Subtype: Link Rect: 243, 105, 255, 114 ActionDest: 168 Page: Sequence: 3 Annotations: Annotation: Subtype: Link Rect: 248, 722, 260, 731 ActionDest: 168 Annotation: Subtype: Link Rect: 292, 609, 304, 618 ActionDest: 168 Annotation: Subtype: Link Rect: 531, 584, 543, 593 ActionDest: 168 Annotation: Subtype: Link Rect: 544, 584, 556, 593 ActionDest: 168 Annotation: Subtype: Link Rect: 515, 559, 527, 568 ActionDest: 168 Annotation: Subtype: Link Rect: 335, 483, 347, 492 ActionDest: 168 Annotation: Subtype: Link Rect: 185, 421, 197, 430 ActionDest: 168 Annotation: Subtype: Link Rect: 418, 358, 430, 367 ActionDest: 168 Annotation: Subtype: Link Rect: 263, 320, 275, 329 ActionDest: 168 Annotation: Subtype: Link Rect: 213, 245, 225, 254 ActionDest: 168 Annotation: Subtype: Link Rect: 225, 245, 237, 254 ActionDest: 168 Annotation: Subtype: Link Rect: 531, 195, 543, 204 ActionDest: 168 Annotation: Subtype: Link Rect: 544, 195, 556, 204 ActionDest: 168 Annotation: Subtype: Link Rect: 496, 157, 508, 166 ActionDest: 168 Annotation: Subtype: Link Rect: 485, 132, 497, 141 ActionDest: 168 Annotation: Subtype: Link Rect: 498, 132, 510, 141 ActionDest: 168 Annotation: Subtype: Link Rect: 328, 82, 340, 91 ActionDest: 168 Annotation: Subtype: Link Rect: 340, 82, 352, 91 ActionDest: 168 Annotation: Subtype: Link Rect: 482, 69, 494, 78 ActionDest: 168 Annotation: Subtype: Link Rect: 494, 69, 506, 78 ActionDest: 168 Page: Sequence: 4 Annotations: Annotation: Subtype: Link Rect: 290, 697, 302, 706 ActionDest: 168 Annotation: Subtype: Link Rect: 302, 697, 314, 706 ActionDest: 168 Annotation: Subtype: Link Rect: 508, 672, 520, 681 ActionDest: 168 Annotation: Subtype: Link Rect: 520, 672, 532, 681 ActionDest: 168 Annotation: Subtype: Link Rect: 532, 672, 544, 681 ActionDest: 168 Annotation: Subtype: Link Rect: 544, 672, 556, 681 ActionDest: 168 Annotation: Subtype: Link Rect: 488, 647, 500, 656 ActionDest: 168 Annotation: Subtype: Link Rect: 500, 647, 512, 656 ActionDest: 168 Annotation: Subtype: Link Rect: 515, 647, 526, 656 ActionDest: 168 Annotation: Subtype: Link Rect: 348, 622, 360, 631 ActionDest: 168 Annotation: Subtype: Link Rect: 299, 597, 311, 606 ActionDest: 168 Annotation: Subtype: Link Rect: 395, 534, 407, 543 ActionDest: 168 Annotation: Subtype: Link Rect: 359, 496, 370, 505 ActionDest: 168 Annotation: Subtype: Link Rect: 371, 496, 383, 505 ActionDest: 171 Annotation: Subtype: Link Rect: 386, 496, 398, 505 ActionDest: 171 Annotation: Subtype: Link Rect: 524, 496, 536, 505 ActionDest: 171 Annotation: Subtype: Link Rect: 464, 471, 476, 480 ActionDest: 168 Annotation: Subtype: Link Rect: 477, 471, 489, 480 ActionDest: 171 Annotation: Subtype: Link Rect: 489, 471, 501, 480 ActionDest: 171 Annotation: Subtype: Link Rect: 507, 446, 519, 455 ActionDest: 171 Annotation: Subtype: Link Rect: 204, 408, 216, 417 ActionDest: 168 Annotation: Subtype: Link Rect: 216, 409, 228, 417 ActionDest: 171 Annotation: Subtype: Link Rect: 203, 396, 215, 405 ActionDest: 168 Annotation: Subtype: Link Rect: 215, 396, 227, 405 ActionDest: 168 Annotation: Subtype: Link Rect: 386, 383, 398, 392 ActionDest: 168 Annotation: Subtype: Link Rect: 379, 346, 391, 355 ActionDest: 171 Annotation: Subtype: Link Rect: 387, 321, 399, 330 ActionDest: 171 Annotation: Subtype: Link Rect: 402, 320, 414, 330 ActionDest: 171 Annotation: Subtype: Link Rect: 382, 295, 394, 304 ActionDest: 168 Annotation: Subtype: Link Rect: 436, 270, 448, 279 ActionDest: 171 Annotation: Subtype: Link Rect: 543, 258, 555, 267 ActionDest: 168 Annotation: Subtype: Link Rect: 224, 233, 236, 242 ActionDest: 168 Annotation: Subtype: Link Rect: 236, 233, 248, 242 ActionDest: 171 Annotation: Subtype: Link Rect: 249, 233, 261, 242 ActionDest: 171 Annotation: Subtype: Link Rect: 404, 182, 416, 191 ActionDest: 168 Annotation: Subtype: Link Rect: 417, 182, 429, 191 ActionDest: 168 Annotation: Subtype: Link Rect: 516, 157, 528, 166 ActionDest: 171 Annotation: Subtype: Link Rect: 353, 69, 365, 78 ActionDest: 171 Page: Sequence: 5 Annotations: Annotation: Subtype: Link Rect: 189, 571, 201, 580 ActionDest: 171 Annotation: Subtype: Link Rect: 253, 508, 265, 518 ActionDest: 171 Annotation: Subtype: Link Rect: 265, 508, 277, 518 ActionDest: 171 Annotation: Subtype: Link Rect: 494, 483, 506, 492 ActionDest: 171 Annotation: Subtype: Link Rect: 239, 446, 251, 455 ActionDest: 171 Annotation: Subtype: Link Rect: 254, 446, 266, 455 ActionDest: 171 Annotation: Subtype: Link Rect: 516, 421, 528, 430 ActionDest: 171 Annotation: Subtype: Link Rect: 529, 421, 541, 430 ActionDest: 171 Annotation: Subtype: Link Rect: 544, 421, 556, 430 ActionDest: 171 Annotation: Subtype: Link Rect: 531, 395, 543, 405 ActionDest: 171 Annotation: Subtype: Link Rect: 544, 395, 556, 405 ActionDest: 171 Annotation: Subtype: Link Rect: 239, 320, 251, 329 ActionDest: 171 Annotation: Subtype: Link Rect: 456, 295, 468, 304 ActionDest: 171 Annotation: Subtype: Link Rect: 352, 207, 364, 216 ActionDest: 171 Annotation: Subtype: Link Rect: 501, 195, 513, 204 ActionDest: 168 Annotation: Subtype: Link Rect: 207, 69, 219, 78 ActionDest: 174 Page: Sequence: 6 Annotations: Annotation: Subtype: Link Rect: 397, 722, 409, 731 ActionDest: 174 Annotation: Subtype: Link Rect: 410, 722, 422, 731 ActionDest: 174 Annotation: Subtype: Link Rect: 496, 659, 508, 669 ActionDest: 174 Annotation: Subtype: Link Rect: 509, 659, 521, 669 ActionDest: 174 Annotation: Subtype: Link Rect: 462, 634, 474, 643 ActionDest: 174 Annotation: Subtype: Link Rect: 213, 597, 225, 606 ActionDest: 171 Annotation: Subtype: Link Rect: 314, 584, 326, 593 ActionDest: 174 Annotation: Subtype: Link Rect: 543, 559, 555, 568 ActionDest: 174 Annotation: Subtype: Link Rect: 264, 521, 276, 530 ActionDest: 174 Annotation: Subtype: Link Rect: 340, 496, 352, 505 ActionDest: 174 Annotation: Subtype: Link Rect: 310, 421, 322, 430 ActionDest: 174 Annotation: Subtype: Link Rect: 405, 396, 417, 405 ActionDest: 174 Annotation: Subtype: Link Rect: 420, 396, 432, 405 ActionDest: 174 Annotation: Subtype: Link Rect: 464, 383, 476, 392 ActionDest: 174 Annotation: Subtype: Link Rect: 525, 383, 537, 392 ActionDest: 174 Annotation: Subtype: Link Rect: 209, 371, 221, 380 ActionDest: 174 Annotation: Subtype: Link Rect: 535, 308, 547, 317 ActionDest: 174 Annotation: Subtype: Link Rect: 202, 283, 214, 292 ActionDest: 174 Annotation: Subtype: Link Rect: 289, 283, 301, 292 ActionDest: 174 Annotation: Subtype: Link Rect: 261, 258, 273, 267 ActionDest: 174 Annotation: Subtype: Link Rect: 273, 258, 285, 267 ActionDest: 174 Annotation: Subtype: Link Rect: 414, 233, 426, 242 ActionDest: 174 Annotation: Subtype: Link Rect: 411, 182, 423, 192 ActionDest: 174 Annotation: Subtype: Link Rect: 186, 157, 198, 166 ActionDest: 174 Annotation: Subtype: Link Rect: 492, 132, 504, 141 ActionDest: 174 Annotation: Subtype: Link Rect: 206, 82, 218, 91 ActionDest: 174 Page: Sequence: 7 Annotations: Annotation: Subtype: Link Rect: 532, 722, 544, 731 ActionDest: 174 Annotation: Subtype: Link Rect: 280, 647, 292, 656 ActionDest: 174 Annotation: Subtype: Link Rect: 415, 569, 422, 581 ActionDest: 130 Annotation: Subtype: Link Rect: 473, 569, 480, 581 ActionDest: 109 Annotation: Subtype: Link Rect: 94, 118, 100, 129 ActionDest: 130 Annotation: Subtype: Link Rect: 118, 118, 125, 129 ActionDest: 147 Page: Sequence: 8 Annotations: Annotation: Subtype: Link Rect: 481, 693, 492, 702 ActionDest: 178 Annotation: Subtype: Link Rect: 495, 693, 506, 702 ActionDest: 178 Annotation: Subtype: Link Rect: 482, 666, 493, 674 ActionDest: 178 Annotation: Subtype: Link Rect: 493, 666, 504, 674 ActionDest: 178 Annotation: Subtype: Link Rect: 482, 639, 493, 647 ActionDest: 174 Annotation: Subtype: Link Rect: 493, 639, 504, 647 ActionDest: 178 Annotation: Subtype: Link Rect: 488, 617, 499, 625 ActionDest: 178 Annotation: Subtype: Link Rect: 488, 595, 499, 603 ActionDest: 178 Annotation: Subtype: Link Rect: 488, 573, 499, 581 ActionDest: 174 Annotation: Subtype: Link Rect: 488, 551, 499, 559 ActionDest: 174 Annotation: Subtype: Link Rect: 488, 513, 499, 521 ActionDest: 174 Annotation: Subtype: Link Rect: 488, 474, 499, 483 ActionDest: 178 Annotation: Subtype: Link Rect: 488, 452, 499, 461 ActionDest: 178 Annotation: Subtype: Link Rect: 488, 436, 499, 444 ActionDest: 178 Annotation: Subtype: Link Rect: 488, 425, 499, 433 ActionDest: 174 Annotation: Subtype: Link Rect: 486, 414, 501, 422 ActionDest: 178 Annotation: Subtype: Link Rect: 486, 403, 501, 411 ActionDest: 178 Annotation: Subtype: Link Rect: 486, 387, 501, 395 ActionDest: 178 Annotation: Subtype: Link Rect: 482, 365, 493, 373 ActionDest: 174 Annotation: Subtype: Link Rect: 493, 365, 504, 373 ActionDest: 174 Annotation: Subtype: Link Rect: 488, 343, 499, 351 ActionDest: 174 Annotation: Subtype: Link Rect: 488, 326, 499, 335 ActionDest: 174 Annotation: Subtype: Link Rect: 486, 315, 501, 324 ActionDest: 178 Annotation: Subtype: Link Rect: 488, 304, 499, 313 ActionDest: 174 Annotation: Subtype: Link Rect: 488, 293, 499, 302 ActionDest: 174 Annotation: Subtype: Link Rect: 486, 282, 501, 291 ActionDest: 178 Annotation: Subtype: Link Rect: 486, 271, 501, 280 ActionDest: 178 Annotation: Subtype: Link Rect: 486, 250, 501, 258 ActionDest: 178 Annotation: Subtype: Link Rect: 488, 222, 499, 231 ActionDest: 174 Annotation: Subtype: Link Rect: 488, 206, 499, 214 ActionDest: 171 Annotation: Subtype: Link Rect: 480, 195, 491, 203 ActionDest: 171 Annotation: Subtype: Link Rect: 491, 195, 507, 203 ActionDest: 178 Annotation: Subtype: Link Rect: 486, 184, 501, 192 ActionDest: 178 Annotation: Subtype: Link Rect: 486, 167, 501, 176 ActionDest: 178 Annotation: Subtype: Link Rect: 488, 135, 499, 143 ActionDest: 171 Annotation: Subtype: Link Rect: 488, 107, 499, 116 ActionDest: 174 Annotation: Subtype: Link Rect: 488, 85, 499, 94 ActionDest: 174 Page: Sequence: 9 Annotations: Annotation: Subtype: Link Rect: 488, 688, 499, 696 ActionDest: 174 Annotation: Subtype: Link Rect: 473, 661, 484, 669 ActionDest: 174 Annotation: Subtype: Link Rect: 487, 661, 498, 669 ActionDest: 174 Annotation: Subtype: Link Rect: 498, 661, 513, 669 ActionDest: 178 Annotation: Subtype: Link Rect: 486, 644, 501, 653 ActionDest: 178 Annotation: Subtype: Link Rect: 482, 633, 493, 642 ActionDest: 174 Annotation: Subtype: Link Rect: 493, 633, 504, 642 ActionDest: 174 Annotation: Subtype: Link Rect: 480, 622, 491, 631 ActionDest: 174 Annotation: Subtype: Link Rect: 491, 622, 507, 631 ActionDest: 178 Annotation: Subtype: Link Rect: 121, 595, 127, 606 ActionDest: 147 Annotation: Subtype: Link Rect: 191, 544, 203, 554 ActionDest: 171 Annotation: Subtype: Link Rect: 203, 545, 220, 554 ActionDest: 178 Annotation: Subtype: Link Rect: 377, 544, 389, 554 ActionDest: 178 Annotation: Subtype: Link Rect: 195, 519, 207, 528 ActionDest: 168 Annotation: Subtype: Link Rect: 208, 520, 220, 528 ActionDest: 171 Annotation: Subtype: Link Rect: 491, 479, 498, 491 ActionDest: 130 Annotation: Subtype: Link Rect: 463, 431, 480, 441 ActionDest: 178 Annotation: Subtype: Link Rect: 204, 394, 216, 403 ActionDest: 174 Annotation: Subtype: Link Rect: 280, 381, 292, 390 ActionDest: 178 Annotation: Subtype: Link Rect: 501, 356, 518, 365 ActionDest: 178 Annotation: Subtype: Link Rect: 511, 293, 528, 302 ActionDest: 178 Annotation: Subtype: Link Rect: 398, 231, 415, 240 ActionDest: 181 Annotation: Subtype: Link Rect: 517, 180, 528, 190 ActionDest: 178 Annotation: Subtype: Link Rect: 452, 168, 469, 177 ActionDest: 181 Annotation: Subtype: Link Rect: 204, 143, 216, 152 ActionDest: 178 Annotation: Subtype: Link Rect: 252, 118, 264, 127 ActionDest: 178 Page: Sequence: 10 Annotations: Annotation: Subtype: Link Rect: 289, 710, 306, 719 ActionDest: 178 Annotation: Subtype: Link Rect: 478, 685, 495, 694 ActionDest: 178 Annotation: Subtype: Link Rect: 461, 647, 473, 656 ActionDest: 174 Annotation: Subtype: Link Rect: 474, 647, 490, 656 ActionDest: 181 Annotation: Subtype: Link Rect: 396, 609, 413, 618 ActionDest: 181 Annotation: Subtype: Link Rect: 448, 572, 465, 581 ActionDest: 181 Annotation: Subtype: Link Rect: 481, 547, 498, 556 ActionDest: 178 Annotation: Subtype: Link Rect: 372, 433, 389, 442 ActionDest: 178 Annotation: Subtype: Link Rect: 389, 433, 406, 442 ActionDest: 181 Annotation: Subtype: Link Rect: 347, 383, 359, 392 ActionDest: 171 Annotation: Subtype: Link Rect: 359, 383, 376, 392 ActionDest: 181 Annotation: Subtype: Link Rect: 376, 383, 393, 392 ActionDest: 181 Annotation: Subtype: Link Rect: 332, 358, 349, 367 ActionDest: 181 Annotation: Subtype: Link Rect: 316, 345, 333, 354 ActionDest: 181 Annotation: Subtype: Link Rect: 203, 333, 215, 342 ActionDest: 171 Annotation: Subtype: Link Rect: 216, 333, 233, 342 ActionDest: 181 Annotation: Subtype: Link Rect: 539, 333, 556, 342 ActionDest: 178 Annotation: Subtype: Link Rect: 519, 308, 536, 317 ActionDest: 181 Annotation: Subtype: Link Rect: 281, 270, 292, 279 ActionDest: 178 Annotation: Subtype: Link Rect: 295, 270, 307, 279 ActionDest: 178 Annotation: Subtype: Link Rect: 401, 257, 412, 267 ActionDest: 178 Annotation: Subtype: Link Rect: 539, 232, 556, 241 ActionDest: 181 Annotation: Subtype: Link Rect: 267, 207, 284, 216 ActionDest: 181 Annotation: Subtype: Link Rect: 515, 195, 532, 204 ActionDest: 181 Annotation: Subtype: Link Rect: 532, 182, 549, 191 ActionDest: 181 Annotation: Subtype: Link Rect: 226, 144, 237, 154 ActionDest: 178 Annotation: Subtype: Link Rect: 218, 132, 235, 141 ActionDest: 181 Annotation: Subtype: Link Rect: 338, 119, 355, 128 ActionDest: 181 Annotation: Subtype: Link Rect: 358, 119, 375, 128 ActionDest: 181 Annotation: Subtype: Link Rect: 452, 107, 469, 116 ActionDest: 181 Annotation: Subtype: Link Rect: 442, 82, 454, 91 ActionDest: 174 Annotation: Subtype: Link Rect: 454, 82, 471, 91 ActionDest: 181 Annotation: Subtype: Link Rect: 472, 82, 489, 91 ActionDest: 181 Page: Sequence: 11 Annotations: Annotation: Subtype: Link Rect: 229, 710, 246, 719 ActionDest: 181 Annotation: Subtype: Link Rect: 286, 622, 303, 631 ActionDest: 181 Annotation: Subtype: Link Rect: 257, 572, 274, 581 ActionDest: 178 Annotation: Subtype: Link Rect: 502, 559, 514, 568 ActionDest: 171 Annotation: Subtype: Link Rect: 309, 445, 326, 454 ActionDest: 181 Annotation: Subtype: Link Rect: 377, 395, 394, 404 ActionDest: 181 Annotation: Subtype: Link Rect: 308, 382, 324, 391 ActionDest: 184 Annotation: Subtype: Link Rect: 198, 319, 215, 328 ActionDest: 184 Annotation: Subtype: Link Rect: 218, 319, 235, 328 ActionDest: 184 Annotation: Subtype: Link Rect: 539, 269, 556, 278 ActionDest: 184 Annotation: Subtype: Link Rect: 285, 219, 302, 228 ActionDest: 184 Annotation: Subtype: Link Rect: 328, 156, 345, 165 ActionDest: 184 Annotation: Subtype: Link Rect: 447, 144, 464, 153 ActionDest: 184 Page: Sequence: 12 Annotations: Annotation: Subtype: Link Rect: 521, 672, 538, 681 ActionDest: 184 Annotation: Subtype: Link Rect: 539, 672, 556, 681 ActionDest: 184 Annotation: Subtype: Link Rect: 206, 622, 223, 631 ActionDest: 184 Annotation: Subtype: Link Rect: 223, 622, 240, 631 ActionDest: 184 Annotation: Subtype: Link Rect: 279, 597, 296, 606 ActionDest: 184 Annotation: Subtype: Link Rect: 233, 521, 250, 530 ActionDest: 184 Annotation: Subtype: Link Rect: 277, 457, 284, 468 ActionDest: 147 Annotation: Subtype: Link Rect: 525, 337, 540, 345 ActionDest: 184 Annotation: Subtype: Link Rect: 525, 310, 540, 318 ActionDest: 184 Annotation: Subtype: Link Rect: 525, 282, 540, 291 ActionDest: 184 Annotation: Subtype: Link Rect: 525, 260, 540, 269 ActionDest: 184 Annotation: Subtype: Link Rect: 525, 238, 540, 247 ActionDest: 184 Annotation: Subtype: Link Rect: 525, 216, 540, 225 ActionDest: 184 Annotation: Subtype: Link Rect: 525, 194, 540, 203 ActionDest: 184 Annotation: Subtype: Link Rect: 525, 173, 540, 181 ActionDest: 184 Annotation: Subtype: Link Rect: 525, 145, 540, 154 ActionDest: 184 Annotation: Subtype: Link Rect: 525, 118, 540, 126 ActionDest: 184 Annotation: Subtype: Link Rect: 525, 96, 540, 104 ActionDest: 184 Page: Sequence: 13 Annotations: Annotation: Subtype: Link Rect: 525, 660, 540, 669 ActionDest: 184 Annotation: Subtype: Link Rect: 525, 633, 540, 641 ActionDest: 184 Annotation: Subtype: Link Rect: 525, 606, 540, 614 ActionDest: 184 Annotation: Subtype: Link Rect: 525, 578, 540, 587 ActionDest: 184 Annotation: Subtype: Link Rect: 527, 551, 538, 559 ActionDest: 178 Annotation: Subtype: Link Rect: 525, 529, 540, 537 ActionDest: 184 Annotation: Subtype: Link Rect: 527, 507, 538, 515 ActionDest: 178 Annotation: Subtype: Link Rect: 525, 485, 540, 493 ActionDest: 184 Annotation: Subtype: Link Rect: 525, 463, 540, 472 ActionDest: 184 Annotation: Subtype: Link Rect: 525, 441, 540, 450 ActionDest: 184 Annotation: Subtype: Link Rect: 525, 419, 540, 428 ActionDest: 184 Annotation: Subtype: Link Rect: 525, 397, 540, 406 ActionDest: 184 Annotation: Subtype: Link Rect: 525, 375, 540, 384 ActionDest: 184 Annotation: Subtype: Link Rect: 525, 354, 540, 362 ActionDest: 184 Annotation: Subtype: Link Rect: 525, 332, 540, 340 ActionDest: 184 Annotation: Subtype: Link Rect: 525, 310, 540, 318 ActionDest: 184 Annotation: Subtype: Link Rect: 525, 288, 540, 296 ActionDest: 184 Annotation: Subtype: Link Rect: 525, 260, 540, 269 ActionDest: 187 Annotation: Subtype: Link Rect: 525, 233, 540, 241 ActionDest: 184 Annotation: Subtype: Link Rect: 525, 211, 540, 219 ActionDest: 187 Annotation: Subtype: Link Rect: 525, 189, 540, 198 ActionDest: 184 Annotation: Subtype: Link Rect: 525, 162, 540, 170 ActionDest: 184 Annotation: Subtype: Link Rect: 525, 134, 540, 143 ActionDest: 184 Annotation: Subtype: Link Rect: 525, 112, 540, 121 ActionDest: 187 Annotation: Subtype: Link Rect: 525, 74, 540, 82 ActionDest: 184 Page: Sequence: 14 Annotations: Annotation: Subtype: Link Rect: 525, 660, 540, 669 ActionDest: 187 Annotation: Subtype: Link Rect: 525, 622, 540, 630 ActionDest: 184 Annotation: Subtype: Link Rect: 525, 600, 540, 608 ActionDest: 184 Annotation: Subtype: Link Rect: 525, 572, 540, 581 ActionDest: 187 Annotation: Subtype: Link Rect: 525, 539, 540, 548 ActionDest: 184 Annotation: Subtype: Link Rect: 525, 507, 540, 515 ActionDest: 187 Annotation: Subtype: Link Rect: 525, 479, 540, 488 ActionDest: 187 Annotation: Subtype: Link Rect: 525, 452, 540, 460 ActionDest: 187 Annotation: Subtype: Link Rect: 525, 419, 540, 427 ActionDest: 187 Annotation: Subtype: Link Rect: 525, 391, 540, 400 ActionDest: 187 Annotation: Subtype: Link Rect: 525, 370, 540, 378 ActionDest: 187 Annotation: Subtype: Link Rect: 525, 348, 540, 356 ActionDest: 187 Annotation: Subtype: Link Rect: 260, 326, 266, 338 ActionDest: 156 Annotation: Subtype: Link Rect: 504, 215, 520, 224 ActionDest: 184 Annotation: Subtype: Link Rect: 521, 215, 538, 224 ActionDest: 187 Annotation: Subtype: Link Rect: 331, 202, 348, 211 ActionDest: 187 Annotation: Subtype: Link Rect: 361, 190, 378, 199 ActionDest: 184 Annotation: Subtype: Link Rect: 431, 127, 448, 136 ActionDest: 187 Annotation: Subtype: Link Rect: 326, 89, 343, 98 ActionDest: 187 Page: Sequence: 15 Annotations: Annotation: Subtype: Link Rect: 533, 666, 548, 674 ActionDest: 187 Annotation: Subtype: Link Rect: 533, 639, 548, 647 ActionDest: 184 Annotation: Subtype: Link Rect: 533, 568, 548, 576 ActionDest: 187 Annotation: Subtype: Link Rect: 533, 496, 548, 505 ActionDest: 187 Annotation: Subtype: Link Rect: 533, 458, 548, 466 ActionDest: 187 Annotation: Subtype: Link Rect: 533, 419, 548, 428 ActionDest: 184 Annotation: Subtype: Link Rect: 533, 392, 548, 400 ActionDest: 187 Annotation: Subtype: Link Rect: 533, 359, 548, 368 ActionDest: 187 Annotation: Subtype: Link Rect: 533, 293, 548, 302 ActionDest: 184 Annotation: Subtype: Link Rect: 484, 112, 491, 124 ActionDest: 156 Annotation: Subtype: Link Rect: 468, 77, 485, 86 ActionDest: 184 Annotation: Subtype: Link Rect: 470, 65, 486, 74 ActionDest: 184 Annotation: Subtype: Link Rect: 487, 65, 504, 74 ActionDest: 184 Annotation: Subtype: Link Rect: 504, 65, 521, 74 ActionDest: 184 Annotation: Subtype: Link Rect: 522, 65, 539, 74 ActionDest: 184 Annotation: Subtype: Link Rect: 539, 65, 556, 74 ActionDest: 184 Page: Sequence: 16 Annotations: Annotation: Subtype: Link Rect: 419, 710, 436, 719 ActionDest: 184 Annotation: Subtype: Link Rect: 437, 710, 454, 719 ActionDest: 184 Annotation: Subtype: Link Rect: 386, 685, 403, 694 ActionDest: 184 Annotation: Subtype: Link Rect: 403, 685, 420, 694 ActionDest: 184 Annotation: Subtype: Link Rect: 508, 672, 525, 681 ActionDest: 184 Annotation: Subtype: Link Rect: 521, 659, 538, 669 ActionDest: 184 Annotation: Subtype: Link Rect: 538, 659, 555, 669 ActionDest: 184 Annotation: Subtype: Link Rect: 290, 634, 307, 643 ActionDest: 184 Annotation: Subtype: Link Rect: 487, 622, 499, 631 ActionDest: 178 Annotation: Subtype: Link Rect: 499, 622, 516, 631 ActionDest: 184 Annotation: Subtype: Link Rect: 517, 622, 534, 631 ActionDest: 184 Annotation: Subtype: Link Rect: 544, 584, 556, 593 ActionDest: 178 Annotation: Subtype: Link Rect: 314, 534, 331, 543 ActionDest: 187 Annotation: Subtype: Link Rect: 486, 484, 503, 493 ActionDest: 187 Annotation: Subtype: Link Rect: 517, 446, 534, 455 ActionDest: 187 Annotation: Subtype: Link Rect: 314, 408, 331, 417 ActionDest: 184 Annotation: Subtype: Link Rect: 331, 408, 348, 417 ActionDest: 184 Annotation: Subtype: Link Rect: 349, 408, 366, 417 ActionDest: 184 Annotation: Subtype: Link Rect: 258, 383, 275, 392 ActionDest: 187 Annotation: Subtype: Link Rect: 538, 371, 555, 380 ActionDest: 187 Annotation: Subtype: Link Rect: 197, 346, 214, 355 ActionDest: 187 Annotation: Subtype: Link Rect: 254, 346, 270, 355 ActionDest: 184 Annotation: Subtype: Link Rect: 402, 346, 419, 355 ActionDest: 184 Annotation: Subtype: Link Rect: 206, 258, 223, 267 ActionDest: 187 Annotation: Subtype: Link Rect: 508, 245, 525, 254 ActionDest: 184 Annotation: Subtype: Link Rect: 270, 220, 287, 229 ActionDest: 184 Annotation: Subtype: Link Rect: 288, 220, 305, 229 ActionDest: 184 Annotation: Subtype: Link Rect: 305, 220, 322, 229 ActionDest: 187 Annotation: Subtype: Link Rect: 498, 220, 515, 229 ActionDest: 184 Annotation: Subtype: Link Rect: 538, 182, 555, 192 ActionDest: 184 Annotation: Subtype: Link Rect: 283, 157, 300, 166 ActionDest: 184 Annotation: Subtype: Link Rect: 431, 145, 448, 154 ActionDest: 187 Annotation: Subtype: Link Rect: 324, 95, 341, 104 ActionDest: 184 Page: Sequence: 17 Annotations: Annotation: Subtype: Link Rect: 410, 722, 427, 731 ActionDest: 184 Annotation: Subtype: Link Rect: 431, 697, 448, 706 ActionDest: 184 Annotation: Subtype: Link Rect: 449, 697, 466, 706 ActionDest: 187 Annotation: Subtype: Link Rect: 540, 697, 557, 706 ActionDest: 184 Annotation: Subtype: Link Rect: 232, 685, 249, 694 ActionDest: 187 Annotation: Subtype: Link Rect: 216, 647, 233, 656 ActionDest: 187 Annotation: Subtype: Link Rect: 268, 622, 285, 631 ActionDest: 184 Annotation: Subtype: Link Rect: 285, 622, 302, 631 ActionDest: 184 Annotation: Subtype: Link Rect: 539, 597, 556, 606 ActionDest: 187 Annotation: Subtype: Link Rect: 409, 572, 426, 581 ActionDest: 187 Annotation: Subtype: Link Rect: 480, 496, 497, 505 ActionDest: 187 Annotation: Subtype: Link Rect: 498, 496, 515, 505 ActionDest: 187 Annotation: Subtype: Link Rect: 539, 484, 556, 492 ActionDest: 187 Annotation: Subtype: Link Rect: 276, 458, 293, 467 ActionDest: 187 Annotation: Subtype: Link Rect: 191, 405, 198, 417 ActionDest: 147 Annotation: Subtype: Link Rect: 442, 94, 459, 103 ActionDest: 187 Page: Sequence: 18 Annotations: Annotation: Subtype: Link Rect: 430, 735, 447, 744 ActionDest: 187 Annotation: Subtype: Link Rect: 311, 722, 323, 731 ActionDest: 174 Annotation: Subtype: Link Rect: 435, 722, 452, 731 ActionDest: 187 Annotation: Subtype: Link Rect: 412, 710, 429, 719 ActionDest: 187 Annotation: Subtype: Link Rect: 444, 685, 461, 694 ActionDest: 187 Annotation: Subtype: Link Rect: 243, 622, 260, 631 ActionDest: 187 Annotation: Subtype: Link Rect: 339, 207, 560, 218 Annotation: Subtype: Link Rect: 56, 196, 95, 207 Annotation: Subtype: Link Rect: 59, 162, 97, 172 Annotation: Subtype: Link Rect: 103, 162, 139, 172 Annotation: Subtype: Link Rect: 59, 127, 97, 137 Annotation: Subtype: Link Rect: 103, 127, 139, 137 Annotation: Subtype: Link Rect: 210, 93, 248, 103 Annotation: Subtype: Link Rect: 519, 80, 557, 91 Annotation: Subtype: Link Rect: 59, 70, 95, 80 Page: Sequence: 19 Annotations: Annotation: Subtype: Link Rect: 218, 722, 256, 732 Annotation: Subtype: Link Rect: 408, 709, 446, 720 Annotation: Subtype: Link Rect: 451, 686, 488, 697 Annotation: Subtype: Link Rect: 440, 663, 478, 674 Annotation: Subtype: Link Rect: 193, 641, 231, 651 Annotation: Subtype: Link Rect: 492, 617, 529, 628 Annotation: Subtype: Link Rect: 140, 584, 178, 594 Annotation: Subtype: Link Rect: 184, 584, 220, 594 Annotation: Subtype: Link Rect: 183, 561, 220, 571 Annotation: Subtype: Link Rect: 226, 561, 262, 571 Annotation: Subtype: Link Rect: 235, 525, 273, 536 Annotation: Subtype: Link Rect: 279, 525, 315, 536 Annotation: Subtype: Link Rect: 167, 503, 204, 513 Annotation: Subtype: Link Rect: 210, 503, 246, 513 Annotation: Subtype: Link Rect: 213, 480, 251, 490 Annotation: Subtype: Link Rect: 366, 456, 403, 467 Annotation: Subtype: Link Rect: 520, 445, 557, 456 Annotation: Subtype: Link Rect: 59, 423, 97, 433 Annotation: Subtype: Link Rect: 472, 410, 509, 421 Annotation: Subtype: Link Rect: 416, 399, 454, 410 Annotation: Subtype: Link Rect: 166, 377, 203, 387 Annotation: Subtype: Link Rect: 209, 377, 245, 387 Annotation: Subtype: Link Rect: 241, 353, 278, 364 Annotation: Subtype: Link Rect: 285, 353, 321, 364 Annotation: Subtype: Link Rect: 160, 331, 197, 341 Annotation: Subtype: Link Rect: 203, 331, 239, 341 Annotation: Subtype: Link Rect: 430, 307, 467, 318 Annotation: Subtype: Link Rect: 481, 284, 518, 295 Annotation: Subtype: Link Rect: 431, 249, 468, 260 Annotation: Subtype: Link Rect: 385, 226, 422, 237 Annotation: Subtype: Link Rect: 376, 215, 413, 226 Annotation: Subtype: Link Rect: 491, 192, 528, 203 Annotation: Subtype: Link Rect: 391, 181, 429, 191 Annotation: Subtype: Link Rect: 409, 157, 446, 168 Annotation: Subtype: Link Rect: 452, 157, 488, 168 Annotation: Subtype: Link Rect: 95, 123, 132, 134 Annotation: Subtype: Link Rect: 139, 123, 175, 134 Annotation: Subtype: Link Rect: 519, 111, 557, 122 Annotation: Subtype: Link Rect: 59, 100, 95, 111 Annotation: Subtype: Link Rect: 254, 77, 292, 88 Page: Sequence: 20 Annotations: Annotation: Subtype: Link Rect: 313, 721, 350, 732 Annotation: Subtype: Link Rect: 172, 698, 209, 709 Annotation: Subtype: Link Rect: 211, 664, 249, 674 Annotation: Subtype: Link Rect: 417, 640, 455, 651 Annotation: Subtype: Link Rect: 104, 618, 141, 628 Annotation: Subtype: Link Rect: 320, 583, 357, 594 Annotation: Subtype: Link Rect: 433, 571, 471, 582 Annotation: Subtype: Link Rect: 519, 548, 557, 559 Annotation: Subtype: Link Rect: 59, 538, 95, 548 Annotation: Subtype: Link Rect: 169, 503, 206, 513 Annotation: Subtype: Link Rect: 212, 503, 248, 513 Annotation: Subtype: Link Rect: 519, 479, 557, 490 Annotation: Subtype: Link Rect: 59, 469, 95, 479 Annotation: Subtype: Link Rect: 59, 446, 97, 456 Annotation: Subtype: Link Rect: 103, 446, 139, 456 Annotation: Subtype: Link Rect: 519, 422, 557, 433 Annotation: Subtype: Link Rect: 59, 411, 95, 421 Annotation: Subtype: Link Rect: 394, 387, 431, 398 Annotation: Subtype: Link Rect: 59, 354, 97, 364 Annotation: Subtype: Link Rect: 494, 341, 531, 352 Annotation: Subtype: Link Rect: 262, 318, 299, 329 Annotation: Subtype: Link Rect: 104, 296, 141, 306 Annotation: Subtype: Link Rect: 148, 296, 184, 306 Annotation: Subtype: Link Rect: 417, 272, 455, 283 Annotation: Subtype: Link Rect: 461, 272, 497, 283 Annotation: Subtype: Link Rect: 345, 249, 383, 260 Annotation: Subtype: Link Rect: 389, 249, 425, 260 Annotation: Subtype: Link Rect: 318, 215, 355, 226 Annotation: Subtype: Link Rect: 361, 215, 397, 226 Annotation: Subtype: Link Rect: 237, 180, 274, 191 Annotation: Subtype: Link Rect: 260, 158, 297, 168 Annotation: Subtype: Link Rect: 309, 134, 346, 145 Annotation: Subtype: Link Rect: 517, 111, 555, 122 Annotation: Subtype: Link Rect: 509, 88, 547, 99 Annotation: Subtype: Link Rect: 163, 65, 201, 76 Page: Sequence: 21 Annotations: Annotation: Subtype: Link Rect: 192, 721, 230, 732 Annotation: Subtype: Link Rect: 236, 721, 272, 732 Annotation: Subtype: Link Rect: 321, 698, 359, 709 Annotation: Subtype: Link Rect: 365, 698, 401, 709 Annotation: Subtype: Link Rect: 272, 675, 309, 686 Annotation: Subtype: Link Rect: 414, 652, 452, 663 Annotation: Subtype: Link Rect: 458, 652, 494, 663 Annotation: Subtype: Link Rect: 520, 629, 557, 640 Annotation: Subtype: Link Rect: 360, 606, 398, 617 Annotation: Subtype: Link Rect: 430, 583, 468, 594 Annotation: Subtype: Link Rect: 442, 560, 479, 571 Annotation: Subtype: Link Rect: 59, 526, 97, 536 Annotation: Subtype: Link Rect: 278, 502, 316, 513 Annotation: Subtype: Link Rect: 104, 469, 141, 479 Annotation: Subtype: Link Rect: 148, 469, 184, 479 Annotation: Subtype: Link Rect: 302, 445, 339, 456 Annotation: Subtype: Link Rect: 346, 445, 382, 456 Annotation: Subtype: Link Rect: 104, 411, 142, 421 Annotation: Subtype: Link Rect: 148, 411, 184, 421 Annotation: Subtype: Link Rect: 59, 377, 97, 387 Annotation: Subtype: Link Rect: 369, 353, 407, 364 Annotation: Subtype: Link Rect: 95, 319, 133, 329 Annotation: Subtype: Link Rect: 212, 296, 250, 306 Annotation: Subtype: Link Rect: 90, 262, 128, 272 Annotation: Subtype: Link Rect: 520, 238, 557, 249 Annotation: Subtype: Link Rect: 187, 215, 225, 226 Annotation: Subtype: Link Rect: 170, 181, 208, 191 Annotation: Subtype: Link Rect: 214, 181, 250, 191 Annotation: Subtype: Link Rect: 439, 157, 477, 168 Annotation: Subtype: Link Rect: 483, 157, 519, 168 Annotation: Subtype: Link Rect: 474, 134, 512, 145 Annotation: Subtype: Link Rect: 174, 112, 212, 122 Annotation: Subtype: Link Rect: 218, 112, 254, 122 Annotation: Subtype: Link Rect: 511, 88, 549, 99 Page: Sequence: 22 Annotations: Annotation: Subtype: Link Rect: 290, 709, 327, 720 Annotation: Subtype: Link Rect: 405, 686, 442, 697 Annotation: Subtype: Link Rect: 339, 652, 377, 663 Annotation: Subtype: Link Rect: 292, 629, 330, 640 Annotation: Subtype: Link Rect: 471, 607, 508, 617 Annotation: Subtype: Link Rect: 362, 583, 400, 594 Annotation: Subtype: Link Rect: 406, 583, 442, 594 Annotation: Subtype: Link Rect: 424, 560, 461, 571 Annotation: Subtype: Link Rect: 467, 560, 503, 571 Annotation: Subtype: Link Rect: 339, 537, 376, 548 Annotation: Subtype: Link Rect: 382, 537, 418, 548 Annotation: Subtype: Link Rect: 350, 514, 387, 525 Annotation: Subtype: Link Rect: 59, 480, 97, 490 Annotation: Subtype: Link Rect: 434, 456, 472, 467 Annotation: Subtype: Link Rect: 247, 410, 284, 421 Annotation: Subtype: Link Rect: 481, 387, 519, 398 Annotation: Subtype: Link Rect: 131, 354, 169, 364 Annotation: Subtype: Link Rect: 59, 319, 97, 329 Annotation: Subtype: Link Rect: 103, 319, 139, 329 Annotation: Subtype: Link Rect: 478, 295, 515, 306 Annotation: Subtype: Link Rect: 521, 295, 557, 306 Annotation: Subtype: Link Rect: 478, 272, 515, 283 Annotation: Subtype: Link Rect: 252, 238, 290, 249 Annotation: Subtype: Link Rect: 296, 238, 332, 249 Annotation: Subtype: Link Rect: 240, 215, 278, 226 Annotation: Subtype: Link Rect: 486, 192, 523, 203 Annotation: Subtype: Link Rect: 397, 169, 435, 180 Annotation: Subtype: Link Rect: 367, 134, 405, 145 Annotation: Subtype: Link Rect: 59, 100, 97, 111 Annotation: Subtype: Link Rect: 59, 66, 97, 76 Page: Sequence: 23 Annotations: Annotation: Subtype: Link Rect: 451, 721, 488, 732 Annotation: Subtype: Link Rect: 495, 721, 531, 732 Annotation: Subtype: Link Rect: 122, 687, 160, 697 Annotation: Subtype: Link Rect: 166, 687, 202, 697 Annotation: Subtype: Link Rect: 342, 664, 379, 674 Annotation: Subtype: Link Rect: 386, 664, 422, 674 Annotation: Subtype: Link Rect: 95, 630, 133, 640 Annotation: Subtype: Link Rect: 397, 606, 435, 617 Annotation: Subtype: Link Rect: 306, 560, 343, 571 Annotation: Subtype: Link Rect: 259, 537, 297, 548 Annotation: Subtype: Link Rect: 498, 514, 536, 525 Annotation: Subtype: Link Rect: 274, 480, 311, 490 Annotation: Subtype: Link Rect: 104, 446, 142, 456 Annotation: Subtype: Link Rect: 519, 422, 557, 433 Annotation: Subtype: Link Rect: 59, 411, 95, 421 Annotation: Subtype: Link Rect: 59, 377, 97, 387 Annotation: Subtype: Link Rect: 103, 377, 139, 387 Annotation: Subtype: Link Rect: 59, 342, 97, 352 Annotation: Subtype: Link Rect: 103, 342, 139, 352 Annotation: Subtype: Link Rect: 298, 318, 336, 329 Annotation: Subtype: Link Rect: 498, 295, 535, 306 Annotation: Subtype: Link Rect: 263, 249, 301, 260 Annotation: Subtype: Link Rect: 187, 215, 224, 226 Annotation: Subtype: Link Rect: 59, 181, 97, 191 Annotation: Subtype: Link Rect: 113, 146, 150, 157 Annotation: Subtype: Link Rect: 213, 111, 251, 122 Annotation: Subtype: Link Rect: 257, 111, 293, 122 Annotation: Subtype: Link Rect: 431, 88, 469, 99 Annotation: Subtype: Link Rect: 475, 88, 511, 99 Page: Sequence: 24 Annotations: Annotation: Subtype: Link Rect: 59, 710, 97, 720 Annotation: Subtype: Link Rect: 103, 710, 139, 720 Annotation: Subtype: Link Rect: 95, 664, 133, 674 Annotation: Subtype: Link Rect: 188, 630, 225, 640 Annotation: Subtype: Link Rect: 220, 607, 257, 617 Annotation: Subtype: Link Rect: 108, 572, 146, 582 Annotation: Subtype: Link Rect: 243, 537, 281, 548 Annotation: Subtype: Link Rect: 172, 503, 209, 513 Annotation: Subtype: Link Rect: 447, 479, 484, 490 Annotation: Subtype: Link Rect: 181, 457, 219, 467 Annotation: Subtype: Link Rect: 225, 457, 261, 467 Annotation: Subtype: Link Rect: 237, 434, 275, 444 Annotation: Subtype: Link Rect: 281, 434, 317, 444 Annotation: Subtype: Link Rect: 360, 399, 397, 410 Annotation: Subtype: Link Rect: 166, 377, 204, 387 Annotation: Subtype: Link Rect: 210, 377, 246, 387 Annotation: Subtype: Link Rect: 250, 342, 288, 352 Annotation: Subtype: Link Rect: 520, 318, 557, 329 Annotation: Subtype: Link Rect: 454, 284, 492, 295 Annotation: Subtype: Link Rect: 440, 261, 478, 272 Annotation: Subtype: Link Rect: 245, 238, 282, 249 Annotation: Subtype: Link Rect: 373, 215, 410, 226 Annotation: Subtype: Link Rect: 416, 192, 454, 203 Annotation: Subtype: Link Rect: 460, 192, 496, 203 Annotation: Subtype: Link Rect: 140, 158, 178, 168 Annotation: Subtype: Link Rect: 184, 158, 220, 168 Annotation: Subtype: Link Rect: 401, 134, 439, 145 Annotation: Subtype: Link Rect: 445, 134, 481, 145 Annotation: Subtype: Link Rect: 336, 112, 374, 122 Annotation: Subtype: Link Rect: 380, 112, 416, 122 Annotation: Subtype: Link Rect: 356, 88, 393, 99 Annotation: Subtype: Link Rect: 400, 88, 436, 99 Page: Sequence: 25 Annotations: Annotation: Subtype: Link Rect: 95, 710, 132, 720 Annotation: Subtype: Link Rect: 463, 686, 500, 697 Annotation: Subtype: Link Rect: 156, 652, 194, 663 Annotation: Subtype: Link Rect: 227, 618, 265, 628 Annotation: Subtype: Link Rect: 391, 594, 429, 605 Annotation: Subtype: Link Rect: 210, 560, 248, 571 Annotation: Subtype: Link Rect: 254, 560, 290, 571 Annotation: Subtype: Link Rect: 187, 525, 224, 536 Annotation: Subtype: Link Rect: 231, 525, 267, 536 Annotation: Subtype: Link Rect: 59, 492, 97, 502 Annotation: Subtype: Link Rect: 59, 457, 97, 467 Annotation: Subtype: Link Rect: 301, 399, 339, 410 Annotation: Subtype: Link Rect: 423, 376, 460, 387 Annotation: Subtype: Link Rect: 446, 353, 484, 364 Annotation: Subtype: Link Rect: 237, 319, 275, 329 Annotation: Subtype: Link Rect: 359, 296, 396, 306 Annotation: Subtype: Link Rect: 59, 262, 97, 272 Annotation: Subtype: Link Rect: 103, 262, 139, 272 Annotation: Subtype: Link Rect: 399, 238, 436, 249 Annotation: Subtype: Link Rect: 442, 238, 478, 249 Annotation: Subtype: Link Rect: 113, 204, 150, 214 Annotation: Subtype: Link Rect: 157, 204, 193, 214 Annotation: Subtype: Link Rect: 411, 169, 448, 180 Annotation: Subtype: Link Rect: 454, 169, 490, 180 Annotation: Subtype: Link Rect: 249, 146, 286, 157 Annotation: Subtype: Link Rect: 451, 123, 489, 134 Annotation: Subtype: Link Rect: 397, 100, 435, 111 Checksum: b965b332 Type: CRC32 Checksum: 289ec402cc167270914050eb4b9575b2 Type: MD5 Checksum: c6f36dfeb141b023cbc8d1c2df144c4471702671 Type: SHA-1