ca58d363d7f632ddb9fa13d32efbc87c pmc_35115992.pdf b515c5d557d4f67bd145b22e3e7074ecd7d54717 pmc_35115992.pdf 3081af639ce2fb2a2ddf3c01dbac550b221d30068f295f2d1b10bfcfef7ae547 pmc_35115992.pdf Title: Pathophysiological Underpinnings of Extra-Motor Neurodegeneration in Amyotrophic Lateral Sclerosis: New Insights From Biomarker Studies Subject: Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) lie at opposing ends of a clinical, genetic, and neuropathological continuum. Keywords: amyotrophic lateral sclerosis (ALS), neuroimage, cerebrospinal fluid (CSF), biomarker (BM), neuropathology, TDP-43 = TAR DNA-binding protein 43, frontotemporal lobar degeneration, frontotemporal dementia (FTD) Author: Ignacio Illán-Gala Creator: LaTeX with hyperref package + hypdvips Producer: dvips + MiKTeX GPL Ghostscript 9.0 CreationDate: Wed Jan 12 12:21:52 2022 CET ModDate: Wed Jan 12 14:09:14 2022 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 19 Encrypted: no Page size: 595.26 x 779.52 pts Page rot: 0 File size: 1218538 bytes Optimized: no PDF version: 1.6 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- JNQHNH+HelveticaNeueLTStd-Bd Type 1C Custom yes yes no 52 0 CUXCAV+HelveticaNeueLTStd-Lt Type 1C Custom yes yes no 57 0 PIAOFJ+HelveticaNeueLTStd-BdIt Type 1C WinAnsi yes yes no 70 0 WVUUWY+HelveticaNeueLTStd-LtIt Type 1C Custom yes yes no 72 0 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NonFullScreenPageMode: UseNone Direction: L2R ViewArea: CropBox ViewClip: CropBox PrintArea: CropBox PageClip: CropBox PageLayout: SinglePage PageMode: UseOutlines Language: en Outlines: Item: Title: Pathophysiological Underpinnings of Extra-Motor Neurodegeneration in Amyotrophic Lateral Sclerosis: New Insights From Biomarke爀 匀琀甀搀椀攀猩㸾൥湤潢樍㘠〠潢樍㰼⽐慲敮琠㔠〠刯乥硴‷‰⁒⽄敳琯獥捴楯渪⸲⽁捴楯港䝯呯⽔楴汥⣾＀䤀渀琀爀漀搀甀挀琀椀漀渀㨀 唀猀椀渀最 䈀椀漀洀愀爀欀攀爀猀 琀漀 刀攀瘀攀愀氀 琀栀攀 䔀砀琀爀愀ⴀ䴀漀琀漀爀 唀渀搀攀爀瀀椀渀渀椀渀最猀 漀昀 䄀洀礀漀琀爀漀瀀栀椀挀 䰀愀琀攀爀愀氀 匀挀氀攀爀漀猀椀猩㸾൥湤潢樍㐴‰扪഼㰯偡牥湴‵‰⁒⽄敳琯獥捴楯渪⸴〯䅣瑩潮⽇潔漯偲敶‴㌠〠刯呩瑬攨References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@76a3e297 Children: Item: Title: Introduction: Using Biomarkers to Reveal the Extra-Motor Underpinnings of Amyotrophic Lateral Sclerosis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4d3167f4 Item: Title: Extra-Motor Involvement in ALS Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@ed9d034 Children: Item: Title: Clinical Evidence for Extra-Motor Involvement in ALS Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6121c9d6 Children: Item: Title: Neuropsychological Evidence Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@87f383f Item: Title: Clinical Evidence Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4eb7f003 Item: Title: Genetic Determinants of Extra-Motor Involvement Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@eafc191 Children: Item: Title: Major Genetic Findings Associated With Extra-Motor Impairment in ALS Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@612fc6eb Item: Title: Genetic Findings Associated With Extra-Motor Sparing in ALS Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1060b431 Item: Title: Neuropathological Underpinnings of Extra-Motor Neurodegeneration Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@612679d6 Children: Item: Title: Neuropathological Changes in ALS Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@11758f2a Item: Title: Neuropathological Correlates of Cognitive and Behavioral Changes in ALS Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@e720b71 Item: Title: Neuroinflammation Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1b26f7b2 Item: Title: Other Neuropathological Hallmarks of ALS: C9orf72, FUS-FET Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@491cc5c9 Item: Title: Biomarkers Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@74ad1f1f Children: Item: Title: Fluid Biomarkers Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6a1aab78 Children: Item: Title: Neurodegeneration Biomarkers Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@462d5aee Item: Title: Synapse Degeneration Markers Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@69b0fd6f Item: Title: Biomarkers Linked to Neuroinflammation and Glial Activation Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@757942a1 Item: Title: Biomarkers Linked to Abnormal TDP-43 Aggregation Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4a87761d Item: Title: Image-Based Biomarkers Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@66d1af89 Children: Item: Title: Macrostructural and Microstructural Changes in MRI Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@8646db9 Item: Title: Functional Magnetic Resonance Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@37374a5e Item: Title: Magnetic Resonance Spectroscopy Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4671e53b Item: Title: PET: 18F-Fluorodeoxyglucose Radiotracer Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@2db7a79b Item: Title: PET to Detect Neuroinflammation Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6950e31 Item: Title: PET to Detect TDP-43 Pathology Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@b7dd107 Item: Title: Other Biomarkers Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@42eca56e Children: Item: Title: Neurophysiological Biomarkers Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@52f759d7 Item: Title: Genetic Biomarkers Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7cbd213e Item: Title: Discussion: Advancing ALS Classification With Biomarkers Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@192d3247 Children: Item: Title: Etiology: Early Identification of TDP-43 Proteinopathies Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@3ecd23d9 Item: Title: Disease Staging: Looking Beyond Corticospinal Tract Neurodegeneration Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@569cfc36 Item: Title: The Relationship Between Astroglial Activity and Disease Progression in the ALS-FTD Continuum Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@43bd930a Item: Title: Beyond TDP-43: Identifying Fast and Slow Progressors Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@33723e30 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@64f6106c Item: Title: Author Contributions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@553a3d88 Item: Title: Funding Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a30d1e6 Item: Title: Acknowledgments Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5891e32e Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@cb0ed20 Info: Title: Pathophysiological Underpinnings of Extra-Motor Neurodegeneration in Amyotrophic Lateral Sclerosis: New Insights From Biomarker Studies Author: Ignacio Illán-Gala Subject: Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) lie at opposing ends of a clinical, genetic, and neuropathological continuum. 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Annotation: Subtype: Link Rect: 270, 193, 285, 204 Destination: External Annotation: Subtype: Link Rect: 97, 124, 113, 135 Destination: External Annotation: Subtype: Link Rect: 116, 124, 131, 135 Destination: External Annotation: Subtype: Link Rect: 200, 78, 216, 90 Destination: External Annotation: Subtype: Link Rect: 219, 78, 234, 90 Destination: External Annotation: Subtype: Link Rect: 483, 363, 499, 375 Destination: External Annotation: Subtype: Link Rect: 503, 363, 518, 375 Destination: External Annotation: Subtype: Link Rect: 393, 239, 404, 250 Destination: External Annotation: Subtype: Link Rect: 408, 239, 424, 250 Destination: External Annotation: Subtype: Link Rect: 483, 204, 494, 216 Destination: External Annotation: Subtype: Link Rect: 497, 204, 508, 216 Destination: External Annotation: Subtype: Link Rect: 511, 204, 527, 216 Destination: External Annotation: Subtype: Link Rect: 530, 204, 546, 216 Destination: External Annotation: Subtype: Link Rect: 354, 135, 365, 147 Destination: External Annotation: Subtype: Link Rect: 368, 135, 383, 147 Destination: External Annotation: Subtype: Link Rect: 43, 29, 111, 37 Annotation: Subtype: Link Rect: 114, 29, 174, 37 Annotation: Subtype: Link Rect: 422, 29, 551, 38 Page: Label: 6 Sequence: 6 Annotations: Annotation: Subtype: Link Rect: 253, 697, 264, 708 Destination: External Annotation: Subtype: Link Rect: 234, 591, 249, 603 Destination: External Annotation: Subtype: Link Rect: 148, 477, 164, 489 Destination: External Annotation: Subtype: Link Rect: 251, 443, 266, 454 Destination: External Annotation: Subtype: Link Rect: 270, 443, 285, 454 Destination: External Annotation: Subtype: Link Rect: 114, 353, 129, 365 Destination: External Annotation: Subtype: Link Rect: 229, 307, 245, 319 Destination: External Annotation: Subtype: Link Rect: 248, 307, 264, 319 Destination: External Annotation: Subtype: Link Rect: 153, 273, 169, 284 Destination: External Annotation: Subtype: Link Rect: 172, 273, 187, 284 Destination: External Annotation: Subtype: Link Rect: 93, 227, 109, 239 Destination: External Annotation: Subtype: Link Rect: 112, 227, 127, 239 Destination: External Annotation: Subtype: Link Rect: 97, 193, 108, 204 Destination: External Annotation: Subtype: Link Rect: 112, 193, 127, 204 Destination: External Annotation: Subtype: Link Rect: 131, 193, 146, 204 Destination: External Annotation: Subtype: Link Rect: 150, 193, 165, 204 Destination: External Annotation: Subtype: Link Rect: 168, 193, 184, 204 Destination: External Annotation: Subtype: Link Rect: 47, 170, 62, 181 Destination: External Annotation: Subtype: Link Rect: 65, 170, 80, 181 Destination: External Annotation: Subtype: Link Rect: 219, 147, 234, 158 Destination: External Annotation: Subtype: Link Rect: 237, 147, 253, 158 Destination: External Annotation: Subtype: Link Rect: 77, 113, 93, 124 Destination: External Annotation: Subtype: Link Rect: 307, 697, 323, 708 Destination: External Annotation: Subtype: Link Rect: 448, 674, 464, 685 Destination: External Annotation: Subtype: Link Rect: 383, 640, 399, 651 Destination: External Annotation: Subtype: Link Rect: 478, 617, 494, 628 Destination: External Annotation: Subtype: Link Rect: 327, 548, 342, 559 Destination: External Annotation: Subtype: Link Rect: 307, 502, 323, 514 Destination: External Annotation: Subtype: Link Rect: 326, 502, 342, 514 Destination: External Annotation: Subtype: Link Rect: 307, 468, 323, 479 Destination: External Annotation: Subtype: Link Rect: 325, 468, 341, 479 Destination: External Annotation: Subtype: Link Rect: 445, 456, 460, 468 Destination: External Annotation: Subtype: Link Rect: 463, 456, 479, 468 Destination: External Annotation: Subtype: Link Rect: 419, 445, 434, 456 Destination: External Annotation: Subtype: Link Rect: 504, 376, 519, 388 Destination: External Annotation: Subtype: Link Rect: 436, 342, 452, 353 Destination: External Annotation: Subtype: Link Rect: 455, 342, 470, 353 Destination: External Annotation: Subtype: Link Rect: 407, 319, 423, 330 Destination: External Annotation: Subtype: Link Rect: 429, 319, 445, 330 Destination: External Annotation: Subtype: Link Rect: 498, 307, 514, 319 Destination: External Annotation: Subtype: Link Rect: 396, 273, 412, 284 Destination: External Annotation: Subtype: Link Rect: 509, 227, 525, 239 Destination: External Annotation: Subtype: Link Rect: 530, 227, 546, 239 Destination: External Annotation: Subtype: Link Rect: 403, 204, 419, 216 Destination: External Annotation: Subtype: Link Rect: 345, 158, 361, 170 Destination: External Annotation: Subtype: Link Rect: 373, 113, 389, 124 Destination: External Annotation: Subtype: Link Rect: 465, 67, 480, 78 Destination: External Annotation: Subtype: Link Rect: 483, 67, 498, 78 Destination: External Annotation: Subtype: Link Rect: 43, 29, 111, 37 Annotation: Subtype: Link Rect: 114, 29, 174, 37 Annotation: Subtype: Link Rect: 422, 29, 551, 38 Page: Label: 7 Sequence: 7 Annotations: Annotation: Subtype: Link Rect: 110, 650, 125, 662 Destination: External Annotation: Subtype: Link Rect: 131, 650, 146, 662 Destination: External Annotation: Subtype: Link Rect: 227, 628, 242, 639 Destination: External Annotation: Subtype: Link Rect: 249, 628, 265, 639 Destination: External Annotation: Subtype: Link Rect: 47, 570, 62, 582 Destination: External Annotation: Subtype: Link Rect: 66, 570, 81, 582 Destination: External Annotation: Subtype: Link Rect: 85, 570, 101, 582 Destination: External Annotation: Subtype: Link Rect: 118, 524, 134, 536 Destination: External Annotation: Subtype: Link Rect: 100, 490, 116, 501 Destination: External Annotation: Subtype: Link Rect: 118, 490, 134, 501 Destination: External Annotation: Subtype: Link Rect: 235, 456, 251, 467 Destination: External Annotation: Subtype: Link Rect: 99, 433, 114, 444 Destination: External Annotation: Subtype: Link Rect: 118, 433, 134, 444 Destination: External Annotation: Subtype: Link Rect: 113, 410, 129, 421 Destination: External Annotation: Subtype: Link Rect: 91, 387, 107, 398 Destination: External Annotation: Subtype: Link Rect: 185, 341, 200, 353 Destination: External Annotation: Subtype: Link Rect: 235, 330, 250, 341 Destination: External Annotation: Subtype: Link Rect: 182, 238, 197, 249 Destination: External Annotation: Subtype: Link Rect: 263, 204, 278, 215 Destination: External Annotation: Subtype: Link Rect: 206, 158, 221, 169 Destination: External Annotation: Subtype: Link Rect: 236, 146, 252, 158 Destination: External Annotation: Subtype: Link Rect: 257, 146, 272, 158 Destination: External Annotation: Subtype: Link Rect: 86, 100, 102, 112 Destination: External Annotation: Subtype: Link Rect: 377, 697, 392, 708 Destination: External Annotation: Subtype: Link Rect: 394, 697, 410, 708 Destination: External Annotation: Subtype: Link Rect: 491, 572, 507, 583 Destination: External Annotation: Subtype: Link Rect: 510, 572, 525, 583 Destination: External Annotation: Subtype: Link Rect: 377, 526, 393, 538 Destination: External Annotation: Subtype: Link Rect: 396, 526, 412, 538 Destination: External Annotation: Subtype: Link Rect: 519, 492, 534, 503 Destination: External Annotation: Subtype: Link Rect: 511, 457, 526, 469 Destination: External Annotation: Subtype: Link Rect: 453, 400, 469, 412 Destination: External Annotation: Subtype: Link Rect: 417, 366, 433, 377 Destination: External Annotation: Subtype: Link Rect: 436, 366, 452, 377 Destination: External Annotation: Subtype: Link Rect: 421, 179, 455, 189 Destination: External Annotation: Subtype: Link Rect: 463, 181, 479, 192 Destination: External Annotation: Subtype: Link Rect: 482, 181, 497, 192 Destination: External Annotation: Subtype: Link Rect: 307, 135, 323, 146 Destination: External Annotation: Subtype: Link Rect: 329, 135, 345, 146 Destination: External Annotation: Subtype: Link Rect: 422, 112, 437, 123 Destination: External Annotation: Subtype: Link Rect: 443, 112, 458, 123 Destination: External Annotation: Subtype: Link Rect: 43, 29, 111, 37 Annotation: Subtype: Link Rect: 114, 29, 174, 37 Annotation: Subtype: Link Rect: 422, 29, 551, 38 Page: Label: 8 Sequence: 8 Annotations: Annotation: Subtype: Link Rect: 47, 330, 62, 341 Destination: External Annotation: Subtype: Link Rect: 65, 330, 80, 341 Destination: External Annotation: Subtype: Link Rect: 147, 296, 162, 307 Destination: External Annotation: Subtype: Link Rect: 208, 262, 224, 274 Destination: External Annotation: Subtype: Link Rect: 229, 262, 245, 274 Destination: External Annotation: Subtype: Link Rect: 120, 228, 135, 240 Destination: External Annotation: Subtype: Link Rect: 47, 194, 62, 206 Destination: External Annotation: Subtype: Link Rect: 65, 194, 81, 206 Destination: External Annotation: Subtype: Link Rect: 47, 126, 62, 137 Destination: External Annotation: Subtype: Link Rect: 68, 126, 83, 137 Destination: External Annotation: Subtype: Link Rect: 86, 126, 102, 137 Destination: External Annotation: Subtype: Link Rect: 530, 341, 546, 352 Destination: External Annotation: Subtype: Link Rect: 354, 295, 369, 306 Destination: External Annotation: Subtype: Link Rect: 372, 295, 387, 306 Destination: External Annotation: Subtype: Link Rect: 390, 295, 406, 306 Destination: External Annotation: Subtype: Link Rect: 432, 192, 448, 204 Destination: External Annotation: Subtype: Link Rect: 451, 192, 466, 204 Destination: External Annotation: Subtype: Link Rect: 353, 146, 368, 158 Destination: External Annotation: Subtype: Link Rect: 329, 90, 345, 101 Destination: External Annotation: Subtype: Link Rect: 400, 90, 416, 101 Destination: External Annotation: Subtype: Link Rect: 43, 29, 111, 37 Annotation: Subtype: Link Rect: 114, 29, 174, 37 Annotation: Subtype: Link Rect: 422, 29, 551, 38 Page: Label: 9 Sequence: 9 Annotations: Annotation: Subtype: Link Rect: 251, 617, 267, 628 Destination: External Annotation: Subtype: Link Rect: 270, 617, 285, 628 Destination: External Annotation: Subtype: Link Rect: 162, 571, 177, 582 Destination: External Annotation: Subtype: Link Rect: 180, 571, 196, 582 Destination: External Annotation: Subtype: Link Rect: 251, 456, 267, 468 Destination: External Annotation: Subtype: Link Rect: 270, 456, 285, 468 Destination: External Annotation: Subtype: Link Rect: 251, 422, 266, 433 Destination: External Annotation: Subtype: Link Rect: 270, 422, 285, 433 Destination: External Annotation: Subtype: Link Rect: 259, 399, 274, 410 Destination: External Annotation: Subtype: Link Rect: 128, 342, 143, 353 Destination: External Annotation: Subtype: Link Rect: 148, 342, 163, 353 Destination: External Annotation: Subtype: Link Rect: 168, 342, 183, 353 Destination: External Annotation: Subtype: Link Rect: 141, 239, 156, 250 Destination: External Annotation: Subtype: Link Rect: 159, 239, 175, 250 Destination: External Annotation: Subtype: Link Rect: 130, 170, 145, 181 Destination: External Annotation: Subtype: Link Rect: 147, 170, 163, 181 Destination: External Annotation: Subtype: Link Rect: 166, 170, 181, 181 Destination: External Annotation: Subtype: Link Rect: 81, 67, 97, 78 Destination: External Annotation: Subtype: Link Rect: 334, 632, 350, 644 Destination: External Annotation: Subtype: Link Rect: 444, 575, 459, 587 Destination: External Annotation: Subtype: Link Rect: 466, 575, 481, 587 Destination: External Annotation: Subtype: Link Rect: 530, 541, 546, 552 Destination: External Annotation: Subtype: Link Rect: 432, 506, 447, 518 Destination: External Annotation: Subtype: Link Rect: 403, 461, 419, 472 Destination: External Annotation: Subtype: Link Rect: 421, 461, 437, 472 Destination: External Annotation: Subtype: Link Rect: 417, 404, 433, 415 Destination: External Annotation: Subtype: Link Rect: 457, 358, 473, 369 Destination: External Annotation: Subtype: Link Rect: 377, 261, 384, 273 Destination: External Annotation: Subtype: Link Rect: 386, 261, 397, 273 Destination: External Annotation: Subtype: Link Rect: 397, 170, 408, 181 Destination: External Annotation: Subtype: Link Rect: 414, 170, 430, 181 Destination: External Annotation: Subtype: Link Rect: 43, 29, 111, 37 Annotation: Subtype: Link Rect: 114, 29, 174, 37 Annotation: Subtype: Link Rect: 422, 29, 551, 38 Page: Label: 10 Sequence: 10 Annotations: Annotation: Subtype: Link Rect: 166, 622, 172, 634 Destination: External Annotation: Subtype: Link Rect: 216, 565, 232, 577 Destination: External Annotation: Subtype: Link Rect: 81, 519, 96, 531 Destination: External Annotation: Subtype: Link Rect: 99, 519, 115, 531 Destination: External Annotation: Subtype: Link Rect: 47, 439, 62, 451 Destination: External Annotation: Subtype: Link Rect: 111, 370, 126, 382 Destination: External Annotation: Subtype: Link Rect: 128, 370, 144, 382 Destination: External Annotation: Subtype: Link Rect: 125, 313, 141, 324 Destination: External Annotation: Subtype: Link Rect: 151, 187, 167, 198 Destination: External Annotation: Subtype: Link Rect: 47, 90, 58, 101 Destination: External Annotation: Subtype: Link Rect: 530, 708, 546, 720 Destination: External Annotation: Subtype: Link Rect: 357, 662, 373, 674 Destination: External Annotation: Subtype: Link Rect: 376, 662, 392, 674 Destination: External Annotation: Subtype: Link Rect: 395, 662, 410, 674 Destination: External Annotation: Subtype: Link Rect: 399, 617, 414, 628 Destination: External Annotation: Subtype: Link Rect: 508, 582, 523, 594 Destination: External Annotation: Subtype: Link Rect: 530, 582, 546, 594 Destination: External Annotation: Subtype: Link Rect: 412, 502, 428, 514 Destination: External Annotation: Subtype: Link Rect: 349, 381, 365, 392 Destination: External Annotation: Subtype: Link Rect: 516, 312, 532, 323 Destination: External Annotation: Subtype: Link Rect: 392, 255, 408, 266 Destination: External Annotation: Subtype: Link Rect: 354, 128, 369, 140 Destination: External Annotation: Subtype: Link Rect: 43, 29, 111, 37 Annotation: Subtype: Link Rect: 114, 29, 174, 37 Annotation: Subtype: Link Rect: 422, 29, 551, 38 Page: Label: 11 Sequence: 11 Annotations: Annotation: Subtype: Link Rect: 78, 422, 89, 433 Destination: External Annotation: Subtype: Link Rect: 96, 422, 112, 433 Destination: External Annotation: Subtype: Link Rect: 183, 388, 198, 399 Destination: External Annotation: Subtype: Link Rect: 121, 342, 136, 353 Destination: External Annotation: Subtype: Link Rect: 107, 296, 123, 307 Destination: External Annotation: Subtype: Link Rect: 125, 296, 141, 307 Destination: External Annotation: Subtype: Link Rect: 55, 156, 89, 166 Destination: External Annotation: Subtype: Link Rect: 339, 582, 355, 594 Destination: External Annotation: Subtype: Link Rect: 421, 110, 498, 121 Annotation: Subtype: Link Rect: 43, 29, 111, 37 Annotation: Subtype: Link Rect: 114, 29, 174, 37 Annotation: Subtype: Link Rect: 422, 29, 551, 38 Page: Label: 12 Sequence: 12 Annotations: Annotation: Subtype: Link Rect: 112, 579, 189, 587 Annotation: Subtype: Link Rect: 210, 561, 289, 569 Annotation: Subtype: Link Rect: 81, 523, 173, 530 Annotation: Subtype: Link Rect: 85, 485, 153, 493 Annotation: Subtype: Link Rect: 167, 457, 270, 464 Annotation: Subtype: Link Rect: 85, 418, 184, 427 Annotation: Subtype: Link Rect: 88, 372, 166, 379 Annotation: Subtype: Link Rect: 163, 332, 231, 341 Annotation: Subtype: Link Rect: 129, 305, 251, 313 Annotation: Subtype: Link Rect: 112, 276, 211, 285 Annotation: Subtype: Link Rect: 159, 247, 224, 256 Annotation: Subtype: Link Rect: 108, 201, 207, 209 Annotation: Subtype: Link Rect: 183, 173, 284, 180 Annotation: Subtype: Link Rect: 88, 135, 177, 142 Annotation: Subtype: Link Rect: 108, 96, 207, 105 Annotation: Subtype: Link Rect: 425, 597, 540, 606 Annotation: Subtype: Link Rect: 345, 550, 425, 559 Annotation: Subtype: Link Rect: 368, 513, 451, 521 Annotation: Subtype: Link Rect: 341, 476, 437, 483 Annotation: Subtype: Link Rect: 403, 446, 484, 455 Annotation: Subtype: Link Rect: 345, 419, 424, 427 Annotation: Subtype: Link Rect: 473, 399, 551, 408 Annotation: Subtype: Link Rect: 372, 342, 471, 351 Annotation: Subtype: Link Rect: 421, 324, 515, 332 Annotation: Subtype: Link Rect: 372, 294, 450, 304 Annotation: Subtype: Link Rect: 434, 267, 519, 275 Annotation: Subtype: Link Rect: 341, 239, 445, 246 Annotation: Subtype: Link Rect: 467, 220, 550, 228 Annotation: Subtype: Link Rect: 382, 192, 478, 199 Annotation: Subtype: Link Rect: 365, 154, 460, 161 Annotation: Subtype: Link Rect: 345, 114, 428, 123 Annotation: Subtype: Link Rect: 375, 78, 479, 85 Annotation: Subtype: Link Rect: 43, 28, 111, 36 Annotation: Subtype: Link Rect: 114, 28, 174, 36 Annotation: Subtype: Link Rect: 422, 28, 551, 37 Page: Label: 13 Sequence: 13 Annotations: Annotation: Subtype: Link Rect: 104, 670, 204, 678 Annotation: Subtype: Link Rect: 85, 632, 173, 640 Annotation: Subtype: Link Rect: 112, 594, 214, 602 Annotation: Subtype: Link Rect: 107, 555, 166, 564 Annotation: Subtype: Link Rect: 292, 508, 60, 527 Annotation: Subtype: Link Rect: 108, 470, 191, 479 Annotation: Subtype: Link Rect: 114, 432, 207, 441 Annotation: Subtype: Link Rect: 163, 396, 242, 403 Annotation: Subtype: Link Rect: 108, 358, 168, 365 Annotation: Subtype: Link Rect: 85, 328, 194, 337 Annotation: Subtype: Link Rect: 185, 300, 254, 309 Annotation: Subtype: Link Rect: 108, 262, 207, 271 Annotation: Subtype: Link Rect: 85, 235, 141, 242 Annotation: Subtype: Link Rect: 85, 206, 170, 214 Annotation: Subtype: Link Rect: 176, 178, 264, 185 Annotation: Subtype: Link Rect: 85, 150, 153, 157 Annotation: Subtype: Link Rect: 104, 102, 200, 110 Annotation: Subtype: Link Rect: 478, 699, 538, 706 Annotation: Subtype: Link Rect: 349, 651, 448, 659 Annotation: Subtype: Link Rect: 552, 612, 320, 631 Annotation: Subtype: Link Rect: 405, 583, 482, 592 Annotation: Subtype: Link Rect: 375, 557, 453, 564 Annotation: Subtype: Link Rect: 372, 517, 454, 526 Annotation: Subtype: Link Rect: 368, 479, 427, 489 Annotation: Subtype: Link Rect: 397, 443, 482, 450 Annotation: Subtype: Link Rect: 345, 396, 430, 403 Annotation: Subtype: Link Rect: 372, 358, 448, 365 Annotation: Subtype: Link Rect: 345, 319, 424, 327 Annotation: Subtype: Link Rect: 345, 292, 430, 299 Annotation: Subtype: Link Rect: 345, 254, 415, 261 Annotation: Subtype: Link Rect: 382, 225, 461, 233 Annotation: Subtype: Link Rect: 372, 187, 476, 195 Annotation: Subtype: Link Rect: 453, 150, 519, 157 Annotation: Subtype: Link Rect: 552, 81, 320, 101 Annotation: Subtype: Link Rect: 43, 29, 111, 37 Annotation: Subtype: Link Rect: 114, 29, 174, 37 Annotation: Subtype: Link Rect: 422, 29, 551, 38 Page: Label: 14 Sequence: 14 Annotations: Annotation: Subtype: Link Rect: 85, 678, 178, 687 Annotation: Subtype: Link Rect: 101, 640, 190, 649 Annotation: Subtype: Link Rect: 108, 604, 208, 612 Annotation: Subtype: Link Rect: 108, 557, 207, 564 Annotation: Subtype: Link Rect: 196, 527, 286, 536 Annotation: Subtype: Link Rect: 85, 489, 179, 498 Annotation: Subtype: Link Rect: 129, 452, 228, 460 Annotation: Subtype: Link Rect: 101, 413, 195, 422 Annotation: Subtype: Link Rect: 104, 375, 183, 384 Annotation: Subtype: Link Rect: 93, 337, 184, 346 Annotation: Subtype: Link Rect: 165, 309, 248, 318 Annotation: Subtype: Link Rect: 97, 263, 196, 271 Annotation: Subtype: Link Rect: 92, 224, 156, 233 Annotation: Subtype: Link Rect: 158, 197, 250, 205 Annotation: Subtype: Link Rect: 190, 169, 276, 176 Annotation: Subtype: Link Rect: 112, 121, 211, 129 Annotation: Subtype: Link Rect: 156, 83, 223, 91 Annotation: Subtype: Link Rect: 365, 678, 448, 687 Annotation: Subtype: Link Rect: 364, 640, 457, 649 Annotation: Subtype: Link Rect: 341, 604, 400, 611 Annotation: Subtype: Link Rect: 348, 557, 416, 564 Annotation: Subtype: Link Rect: 436, 527, 519, 536 Annotation: Subtype: Link Rect: 341, 489, 456, 498 Annotation: Subtype: Link Rect: 341, 452, 441, 460 Annotation: Subtype: Link Rect: 368, 415, 444, 422 Annotation: Subtype: Link Rect: 445, 386, 503, 394 Annotation: Subtype: Link Rect: 345, 347, 430, 356 Annotation: Subtype: Link Rect: 466, 320, 551, 327 Annotation: Subtype: Link Rect: 425, 281, 507, 290 Annotation: Subtype: Link Rect: 465, 254, 546, 261 Annotation: Subtype: Link Rect: 430, 225, 515, 233 Annotation: Subtype: Link Rect: 552, 177, 320, 196 Annotation: Subtype: Link Rect: 345, 150, 430, 157 Annotation: Subtype: Link Rect: 345, 112, 430, 119 Annotation: Subtype: Link Rect: 412, 82, 471, 91 Annotation: Subtype: Link Rect: 43, 29, 111, 37 Annotation: Subtype: Link Rect: 114, 29, 174, 37 Annotation: Subtype: Link Rect: 422, 29, 551, 38 Page: Label: 15 Sequence: 15 Annotations: Annotation: Subtype: Link Rect: 292, 677, 60, 698 Annotation: Subtype: Link Rect: 129, 642, 214, 649 Annotation: Subtype: Link Rect: 112, 612, 204, 621 Annotation: Subtype: Link Rect: 108, 576, 193, 583 Annotation: Subtype: Link Rect: 186, 547, 290, 554 Annotation: Subtype: Link Rect: 108, 508, 172, 517 Annotation: Subtype: Link Rect: 85, 471, 170, 479 Annotation: Subtype: Link Rect: 88, 441, 181, 451 Annotation: Subtype: Link Rect: 85, 405, 145, 413 Annotation: Subtype: Link Rect: 150, 386, 236, 394 Annotation: Subtype: Link Rect: 173, 367, 258, 375 Annotation: Subtype: Link Rect: 81, 320, 170, 327 Annotation: Subtype: Link Rect: 81, 263, 204, 271 Annotation: Subtype: Link Rect: 97, 234, 193, 243 Annotation: Subtype: Link Rect: 85, 195, 165, 205 Annotation: Subtype: Link Rect: 292, 147, 60, 168 Annotation: Subtype: Link Rect: 115, 112, 200, 119 Annotation: Subtype: Link Rect: 120, 72, 211, 81 Annotation: Subtype: Link Rect: 345, 680, 434, 687 Annotation: Subtype: Link Rect: 368, 650, 439, 659 Annotation: Subtype: Link Rect: 366, 613, 449, 621 Annotation: Subtype: Link Rect: 402, 574, 488, 583 Annotation: Subtype: Link Rect: 350, 538, 439, 545 Annotation: Subtype: Link Rect: 368, 500, 457, 507 Annotation: Subtype: Link Rect: 345, 471, 430, 479 Annotation: Subtype: Link Rect: 462, 443, 545, 451 Annotation: Subtype: Link Rect: 429, 422, 511, 432 Annotation: Subtype: Link Rect: 354, 386, 439, 394 Annotation: Subtype: Link Rect: 389, 356, 478, 366 Annotation: Subtype: Link Rect: 393, 318, 487, 328 Annotation: Subtype: Link Rect: 438, 282, 527, 289 Annotation: Subtype: Link Rect: 365, 243, 448, 252 Annotation: Subtype: Link Rect: 552, 196, 320, 215 Annotation: Subtype: Link Rect: 345, 157, 428, 166 Annotation: Subtype: Link Rect: 368, 121, 426, 129 Annotation: Subtype: Link Rect: 460, 93, 514, 100 Annotation: Subtype: Link Rect: 43, 29, 111, 37 Annotation: Subtype: Link Rect: 114, 29, 174, 37 Annotation: Subtype: Link Rect: 422, 29, 551, 38 Page: Label: 16 Sequence: 16 Annotations: Annotation: Subtype: Link Rect: 108, 699, 212, 706 Annotation: Subtype: Link Rect: 108, 650, 194, 659 Annotation: Subtype: Link Rect: 118, 613, 222, 621 Annotation: Subtype: Link Rect: 118, 574, 212, 583 Annotation: Subtype: Link Rect: 93, 538, 172, 545 Annotation: Subtype: Link Rect: 225, 509, 280, 517 Annotation: Subtype: Link Rect: 85, 471, 188, 479 Annotation: Subtype: Link Rect: 112, 434, 215, 441 Annotation: Subtype: Link Rect: 81, 394, 164, 403 Annotation: Subtype: Link Rect: 112, 358, 215, 365 Annotation: Subtype: Link Rect: 218, 329, 272, 337 Annotation: Subtype: Link Rect: 108, 301, 193, 308 Annotation: Subtype: Link Rect: 129, 272, 228, 280 Annotation: Subtype: Link Rect: 108, 243, 191, 252 Annotation: Subtype: Link Rect: 101, 206, 189, 214 Annotation: Subtype: Link Rect: 126, 167, 209, 176 Annotation: Subtype: Link Rect: 129, 140, 211, 148 Annotation: Subtype: Link Rect: 292, 92, 60, 111 Annotation: Subtype: Link Rect: 345, 699, 448, 706 Annotation: Subtype: Link Rect: 345, 661, 441, 668 Annotation: Subtype: Link Rect: 451, 631, 545, 640 Annotation: Subtype: Link Rect: 372, 604, 486, 612 Annotation: Subtype: Link Rect: 371, 566, 475, 573 Annotation: Subtype: Link Rect: 437, 527, 502, 536 Annotation: Subtype: Link Rect: 365, 479, 451, 489 Annotation: Subtype: Link Rect: 368, 441, 462, 451 Annotation: Subtype: Link Rect: 345, 415, 408, 422 Annotation: Subtype: Link Rect: 464, 386, 524, 394 Annotation: Subtype: Link Rect: 386, 358, 471, 365 Annotation: Subtype: Link Rect: 390, 328, 504, 337 Annotation: Subtype: Link Rect: 415, 299, 506, 308 Annotation: Subtype: Link Rect: 368, 263, 430, 271 Annotation: Subtype: Link Rect: 368, 233, 457, 243 Annotation: Subtype: Link Rect: 420, 195, 502, 204 Annotation: Subtype: Link Rect: 552, 158, 320, 177 Annotation: Subtype: Link Rect: 492, 129, 551, 138 Annotation: Subtype: Link Rect: 393, 93, 478, 100 Annotation: Subtype: Link Rect: 43, 29, 111, 37 Annotation: Subtype: Link Rect: 114, 29, 174, 37 Annotation: Subtype: Link Rect: 422, 29, 551, 38 Page: Label: 17 Sequence: 17 Annotations: Annotation: Subtype: Link Rect: 180, 697, 276, 706 Annotation: Subtype: Link Rect: 292, 650, 60, 669 Annotation: Subtype: Link Rect: 165, 612, 252, 621 Annotation: Subtype: Link Rect: 112, 574, 193, 583 Annotation: Subtype: Link Rect: 85, 546, 184, 555 Annotation: Subtype: Link Rect: 163, 519, 251, 526 Annotation: Subtype: Link Rect: 81, 470, 185, 479 Annotation: Subtype: Link Rect: 108, 433, 173, 441 Annotation: Subtype: Link Rect: 85, 396, 189, 403 Annotation: Subtype: Link Rect: 81, 358, 194, 366 Annotation: Subtype: Link Rect: 85, 320, 143, 327 Annotation: Subtype: Link Rect: 292, 281, 60, 300 Annotation: Subtype: Link Rect: 85, 243, 149, 252 Annotation: Subtype: Link Rect: 292, 194, 60, 215 Annotation: Subtype: Link Rect: 292, 156, 60, 177 Annotation: Subtype: Link Rect: 112, 110, 191, 119 Annotation: Subtype: Link Rect: 112, 74, 200, 81 Annotation: Subtype: Link Rect: 354, 680, 439, 687 Annotation: Subtype: Link Rect: 345, 640, 448, 649 Annotation: Subtype: Link Rect: 552, 592, 320, 613 Annotation: Subtype: Link Rect: 443, 566, 528, 573 Annotation: Subtype: Link Rect: 372, 528, 457, 536 Annotation: Subtype: Link Rect: 341, 481, 401, 488 Annotation: Subtype: Link Rect: 348, 452, 434, 460 Annotation: Subtype: Link Rect: 452, 424, 514, 431 Annotation: Subtype: Link Rect: 427, 396, 488, 403 Annotation: Subtype: Link Rect: 366, 348, 456, 356 Annotation: Subtype: Link Rect: 375, 310, 435, 318 Annotation: Subtype: Link Rect: 386, 273, 473, 280 Annotation: Subtype: Link Rect: 341, 244, 446, 252 Annotation: Subtype: Link Rect: 371, 206, 475, 214 Annotation: Subtype: Link Rect: 348, 178, 448, 185 Annotation: Subtype: Link Rect: 345, 140, 441, 148 Annotation: Subtype: Link Rect: 350, 110, 429, 119 Annotation: Subtype: Link Rect: 372, 72, 459, 81 Annotation: Subtype: Link Rect: 43, 29, 111, 37 Annotation: Subtype: Link Rect: 114, 29, 174, 37 Annotation: Subtype: Link Rect: 422, 29, 551, 38 Page: Label: 18 Sequence: 18 Annotations: Annotation: Subtype: Link Rect: 211, 687, 291, 697 Annotation: Subtype: Link Rect: 112, 661, 225, 668 Annotation: Subtype: Link Rect: 112, 621, 195, 630 Annotation: Subtype: Link Rect: 105, 585, 196, 593 Annotation: Subtype: Link Rect: 85, 547, 153, 555 Annotation: Subtype: Link Rect: 226, 528, 279, 536 Annotation: Subtype: Link Rect: 90, 490, 175, 498 Annotation: Subtype: Link Rect: 85, 452, 188, 460 Annotation: Subtype: Link Rect: 108, 413, 187, 422 Annotation: Subtype: Link Rect: 108, 377, 164, 384 Annotation: Subtype: Link Rect: 88, 339, 192, 346 Annotation: Subtype: Link Rect: 153, 311, 215, 318 Annotation: Subtype: Link Rect: 166, 271, 270, 280 Annotation: Subtype: Link Rect: 111, 235, 180, 243 Annotation: Subtype: Link Rect: 292, 194, 60, 215 Annotation: Subtype: Link Rect: 150, 167, 264, 176 Annotation: Subtype: Link Rect: 126, 129, 209, 138 Annotation: Subtype: Link Rect: 115, 93, 218, 100 Annotation: Subtype: Link Rect: 97, 74, 177, 82 Annotation: Subtype: Link Rect: 345, 678, 446, 687 Annotation: Subtype: Link Rect: 398, 641, 498, 649 Annotation: Subtype: Link Rect: 361, 604, 446, 612 Annotation: Subtype: Link Rect: 423, 574, 504, 583 Annotation: Subtype: Link Rect: 345, 538, 434, 545 Annotation: Subtype: Link Rect: 458, 508, 551, 517 Annotation: Subtype: Link Rect: 345, 470, 422, 479 Annotation: Subtype: Link Rect: 371, 434, 475, 441 Annotation: Subtype: Link Rect: 341, 394, 398, 403 Annotation: Subtype: Link Rect: 345, 357, 444, 366 Annotation: Subtype: Link Rect: 372, 319, 471, 328 Annotation: Subtype: Link Rect: 415, 292, 467, 299 Annotation: Subtype: Link Rect: 357, 252, 440, 261 Annotation: Subtype: Link Rect: 361, 225, 465, 233 Annotation: Subtype: Link Rect: 552, 186, 320, 205 Annotation: Subtype: Link Rect: 357, 148, 444, 157 Annotation: Subtype: Link Rect: 552, 100, 320, 120 Annotation: Subtype: Link Rect: 43, 29, 111, 37 Annotation: Subtype: Link Rect: 114, 29, 174, 37 Annotation: Subtype: Link Rect: 422, 29, 551, 38 Page: Label: 19 Sequence: 19 Annotations: Annotation: Subtype: Link Rect: 292, 698, 60, 716 Annotation: Subtype: Link Rect: 126, 670, 184, 678 Annotation: Subtype: Link Rect: 160, 640, 253, 649 Annotation: Subtype: Link Rect: 81, 621, 188, 631 Annotation: Subtype: Link Rect: 292, 582, 60, 603 Annotation: Subtype: Link Rect: 292, 546, 60, 565 Annotation: Subtype: Link Rect: 157, 519, 224, 526 Annotation: Subtype: Link Rect: 108, 470, 207, 479 Annotation: Subtype: Link Rect: 81, 434, 185, 441 Annotation: Subtype: Link Rect: 115, 396, 218, 403 Annotation: Subtype: Link Rect: 108, 366, 195, 375 Annotation: Subtype: Link Rect: 189, 339, 250, 347 Annotation: Subtype: Link Rect: 185, 320, 251, 328 Annotation: Subtype: Link Rect: 97, 292, 176, 299 Annotation: Subtype: Link Rect: 85, 252, 167, 261 Annotation: Subtype: Link Rect: 206, 235, 275, 243 Annotation: Subtype: Link Rect: 111, 197, 200, 204 Annotation: Subtype: Link Rect: 219, 169, 279, 176 Annotation: Subtype: Link Rect: 115, 121, 200, 129 Annotation: Subtype: Link Rect: 552, 696, 320, 717 Annotation: Subtype: Link Rect: 552, 660, 320, 679 Annotation: Subtype: Link Rect: 375, 623, 444, 631 Annotation: Subtype: Link Rect: 390, 585, 448, 592 Annotation: Subtype: Link Rect: 403, 547, 491, 554 Annotation: Subtype: Link Rect: 368, 509, 472, 517 Annotation: Subtype: Link Rect: 365, 471, 479, 479 Annotation: Subtype: Link Rect: 372, 434, 476, 441 Annotation: Subtype: Link Rect: 375, 396, 447, 403 Annotation: Subtype: Link Rect: 487, 367, 542, 375 Annotation: Subtype: Link Rect: 382, 328, 476, 337 Annotation: Subtype: Link Rect: 368, 292, 472, 299 Annotation: Subtype: Link Rect: 492, 149, 519, 156 Annotation: Subtype: Link Rect: 519, 149, 551, 156 Annotation: Subtype: Link Rect: 304, 140, 339, 147 Annotation: Subtype: Link Rect: 339, 140, 362, 147 Annotation: Subtype: Link Rect: 362, 139, 390, 147 Annotation: Subtype: Link Rect: 43, 29, 111, 37 Annotation: Subtype: Link Rect: 114, 29, 174, 37 Annotation: Subtype: Link Rect: 422, 29, 551, 38 Checksum: 43e9b903 Type: CRC32 Checksum: ca58d363d7f632ddb9fa13d32efbc87c Type: MD5 Checksum: b515c5d557d4f67bd145b22e3e7074ecd7d54717 Type: SHA-1