a9b8d5b50fda357d4f3cce86ba4ab6f8 271979.pdf 385818e871d8251aa9852eb73ac8f9249d961043 271979.pdf 5c887c552fc453fb6d088b13de49e61f886d8493fcd38e076df3e01afb9f406b 271979.pdf Title: Autoimmune Rheumatic Diseases: An Update on the Role of Atherogenic Electronegative LDL and Potential Therapeutic Strategies Subject: Atherosclerosis has been linked with an increased risk of atherosclerotic cardiovascular disease (ASCVD). Autoimmune rheumatic diseases (AIRDs) are associated with accelerated atherosclerosis and ASCVD. However, the mechanisms underlying the high ASCVD burden in patients with AIRDs cannot be explained only by conventional risk factors despite disease-specific factors and chronic inflammation. Nevertheless, the normal levels of plasma low-density lipoprotein (LDL) cholesterol observed in most patients with AIRDs do not exclude the possibility of increased LDL atherogenicity. By using anion-exchange chromatography, human LDL can be divided into five increasingly electronegative subfractions, L1 to L5, or into electropositive and electronegative counterparts, LDL (+) and LDL (-). Electronegative L5 and LDL (-) have similar chemical compositions and can induce adverse inflammatory reactions in vascular cells. Notably, the percentage of L5 or LDL (-) in total LDL is increased in normolipidemic patients with AIRDs. Electronegative L5 and LDL (-) are not recognized by the normal LDL receptor but instead signal through the lectin-like oxidized LDL receptor 1 (LOX-1) to activate inflammasomes involving interleukin 1 (IL-1). Here, we describe the detailed mechanisms of AIRD-related ASCVD mediated by L5 or LDL (-) and discuss the potential targeting of LOX-1 or IL-1 signaling as new therapeutic modalities for these diseases. Keywords: electronegative LDL; L5; atherosclerotic cardiovascular disease (ASCVD); autoimmune rheumatic diseases (AIRDs); lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1); interleukin 1 (IL-1) Author: Der-Yuan Chen, Tatsuya Sawamura, Richard A. F. Dixon, José Luis Sánchez-Quesada and Chu-Huang Chen Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Thu May 6 12:04:41 2021 CEST ModDate: Thu May 6 12:06:51 2021 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 15 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1303397 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- LHCXDL+EURM10 Type 1 Builtin yes yes no 10 0 DPHYST+URWPalladioL-Ital Type 1 Custom yes yes no 14 0 VRHGPR+URWPalladioL-Bold Type 1 Custom yes yes no 19 0 VDASVX+URWPalladioL-Roma Type 1 Custom yes yes no 23 0 SAUAIP+CMSY10 Type 1 Builtin yes yes no 27 0 GIFXFT+VnURWPalladioL-Bold Type 1 Custom yes yes no 31 0 XPUSBJ+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 40 0 BSDWLC+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 43 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 65 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 69 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 73 0 HLIJHP+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 104 0 HLIJIA+PalatinoLinotype CID TrueType Identity-H yes yes yes 107 0 HLIJIB+PalatinoLinotype TrueType WinAnsi yes yes no 113 0 HLIJJC+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 116 0 HLIJHP+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 133 0 HLIJIA+PalatinoLinotype CID TrueType Identity-H yes yes yes 136 0 HLIJIB+PalatinoLinotype TrueType WinAnsi yes yes no 142 0 HLIJJC+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 145 0 FNEURI+VnURWPalladioL Type 1 Custom yes yes no 152 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-05-24 02:31:00 CEST RepresentationInformation: 271979.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-05-23 15:39:54 CEST Size: 1303397 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 593 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: Epidemiology of ASCVD in Patients with AIRDs Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Item: Title: Electronegative LDL and Its Atherogenicity Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Children: Item: Title: The Atherogenic Mechanisms of Electronegative LDL Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: The Assocation of Electronegative LDL with ASCVD in Patients with AIRDs Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: Combined Atherogenicity of Electronegative VLDL and LDL Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Role of LOX-1 in Electronegative LDL Signaling Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Children: Item: Title: The Potential Atherogenic Role of LOX-1 in Patients with AIRDs Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: Atherogenic Signaling of Electronegative LDL and LOX-1 in Patients with AIRDs Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: Proposed Therapeutic Strategies for Targeting ASCVD in Patients with AIRDs Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Children: Item: Title: Modifications of Traditional CVD Risk Factors Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Tight Control of Disease Activity and the Adjustment of Medications Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: Lipid-Lowering Therapy Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: Potential Therapeutic Strategy Targeting Electronegative LDL and LOX-1 Pathway Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Info: Title: Autoimmune Rheumatic Diseases: An Update on the Role of Atherogenic Electronegative LDL and Potential Therapeutic Strategies Author: Der-Yuan Chen, Tatsuya Sawamura, Richard A. F. Dixon, José Luis Sánchez-Quesada and Chu-Huang Chen Subject: Atherosclerosis has been linked with an increased risk of atherosclerotic cardiovascular disease (ASCVD). Autoimmune rheumatic diseases (AIRDs) are associated with accelerated atherosclerosis and ASCVD. However, the mechanisms underlying the high ASCVD burden in patients with AIRDs cannot be explained only by conventional risk factors despite disease-specific factors and chronic inflammation. Nevertheless, the normal levels of plasma low-density lipoprotein (LDL) cholesterol observed in most patients with AIRDs do not exclude the possibility of increased LDL atherogenicity. By using anion-exchange chromatography, human LDL can be divided into five increasingly electronegative subfractions, L1 to L5, or into electropositive and electronegative counterparts, LDL (+) and LDL (-). Electronegative L5 and LDL (-) have similar chemical compositions and can induce adverse inflammatory reactions in vascular cells. Notably, the percentage of L5 or LDL (-) in total LDL is increased in normolipidemic patients with AIRDs. Electronegative L5 and LDL (-) are not recognized by the normal LDL receptor but instead signal through the lectin-like oxidized LDL receptor 1 (LOX-1) to activate inflammasomes involving interleukin 1 (IL-1). Here, we describe the detailed mechanisms of AIRD-related ASCVD mediated by L5 or LDL (-) and discuss the potential targeting of LOX-1 or IL-1 signaling as new therapeutic modalities for these diseases. Keywords: electronegative LDL; L5; atherosclerotic cardiovascular disease (ASCVD); autoimmune rheumatic diseases (AIRDs); lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1); interleukin 1 (IL-1) Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Thu May 06 12:04:41 CEST 2021 ModDate: Thu May 06 12:06:51 CEST 2021 ID: 0x26d45e3cd48ce19b3f0576ca625e64d2, 0x26d45e3cd48ce19b3f0576ca625e64d2 Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: VRHGPR+URWPalladioL-Bold FontSubset: true FirstChar: 3 LastChar: 122 FontDescriptor: FontName: VRHGPR+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: VDASVX+URWPalladioL-Roma FontSubset: true FirstChar: 2 LastChar: 246 FontDescriptor: FontName: VDASVX+URWPalladioL-Roma Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: FNEURI+VnURWPalladioL FontSubset: true FirstChar: 157 LastChar: 243 FontDescriptor: FontName: FNEURI+VnURWPalladioL Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: LHCXDL+EURM10 FontSubset: true FirstChar: 11 LastChar: 20 FontDescriptor: FontName: LHCXDL+EURM10 Flags: Symbolic FontBBox: -32, -243, 1060, 720 FontFile: true Font: BaseFont: SAUAIP+CMSY10 FontSubset: true FirstChar: 0 LastChar: 48 FontDescriptor: FontName: SAUAIP+CMSY10 Flags: Symbolic FontBBox: -29, -960, 1116, 775 FontFile: true Font: BaseFont: DPHYST+URWPalladioL-Ital FontSubset: true FirstChar: 2 LastChar: 121 FontDescriptor: FontName: DPHYST+URWPalladioL-Ital Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: GIFXFT+VnURWPalladioL-Bold FontSubset: true FirstChar: 161 LastChar: 178 FontDescriptor: FontName: GIFXFT+VnURWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Pages: Page: Sequence: 1 Annotations: Annotation: Subtype: Link Rect: 35, 759, 176, 795 Annotation: Subtype: Link Rect: 515, 759, 560, 795 Annotation: Subtype: Link Rect: 472, 641, 483, 654 Annotation: Subtype: Link Rect: 115, 346, 154, 355 Annotation: Subtype: Link Rect: 35, 334, 129, 343 Annotation: Subtype: Link Rect: 35, 162, 97, 184 Annotation: Subtype: Link Rect: 153, 89, 154, 98 Annotation: Subtype: Link Rect: 35, 77, 147, 86 Annotation: Subtype: Link Rect: 318, 78, 325, 87 ActionDest: 149 Annotation: Subtype: Link Rect: 131, 17, 268, 28 Annotation: Subtype: Link Rect: 422, 17, 558, 28 Annotation: Subtype: Link Rect: 35, 435, 87, 454 Page: Sequence: 2 Annotations: Annotation: Subtype: Link Rect: 296, 724, 303, 733 ActionDest: 149 Annotation: Subtype: Link Rect: 282, 699, 289, 708 ActionDest: 149 Annotation: Subtype: Link Rect: 292, 699, 299, 708 ActionDest: 149 Annotation: Subtype: Link Rect: 549, 686, 556, 695 ActionDest: 149 Annotation: Subtype: Link Rect: 252, 649, 259, 658 ActionDest: 149 Annotation: Subtype: Link Rect: 262, 649, 274, 658 ActionDest: 156 Annotation: Subtype: Link Rect: 463, 636, 475, 645 ActionDest: 156 Annotation: Subtype: Link Rect: 196, 624, 208, 633 ActionDest: 156 Annotation: Subtype: Link Rect: 475, 624, 487, 633 ActionDest: 156 Annotation: Subtype: Link Rect: 246, 599, 258, 608 ActionDest: 156 Annotation: Subtype: Link Rect: 313, 561, 325, 570 ActionDest: 156 Annotation: Subtype: Link Rect: 224, 548, 236, 557 ActionDest: 156 Annotation: Subtype: Link Rect: 239, 548, 251, 557 ActionDest: 156 Annotation: Subtype: Link Rect: 395, 536, 406, 545 ActionDest: 156 Annotation: Subtype: Link Rect: 407, 536, 419, 545 ActionDest: 156 Annotation: Subtype: Link Rect: 311, 485, 322, 495 ActionDest: 156 Annotation: Subtype: Link Rect: 214, 460, 225, 469 ActionDest: 156 Annotation: Subtype: Link Rect: 198, 423, 210, 432 ActionDest: 156 Annotation: Subtype: Link Rect: 320, 410, 332, 419 ActionDest: 156 Annotation: Subtype: Link Rect: 466, 385, 478, 394 ActionDest: 156 Annotation: Subtype: Link Rect: 478, 385, 490, 394 ActionDest: 156 Annotation: Subtype: Link Rect: 265, 360, 277, 369 ActionDest: 159 Annotation: Subtype: Link Rect: 458, 360, 470, 369 ActionDest: 159 Annotation: Subtype: Link Rect: 473, 360, 485, 369 ActionDest: 159 Annotation: Subtype: Link Rect: 203, 348, 215, 356 ActionDest: 159 Annotation: Subtype: Link Rect: 216, 348, 228, 356 ActionDest: 159 Annotation: Subtype: Link Rect: 271, 347, 283, 356 ActionDest: 159 Annotation: Subtype: Link Rect: 449, 348, 461, 356 ActionDest: 159 Annotation: Subtype: Link Rect: 276, 335, 288, 344 ActionDest: 159 Annotation: Subtype: Link Rect: 289, 335, 301, 344 ActionDest: 159 Annotation: Subtype: Link Rect: 422, 335, 434, 344 ActionDest: 159 Annotation: Subtype: Link Rect: 215, 310, 227, 319 ActionDest: 159 Annotation: Subtype: Link Rect: 285, 297, 297, 306 ActionDest: 159 Annotation: Subtype: Link Rect: 544, 259, 556, 269 ActionDest: 159 Annotation: Subtype: Link Rect: 250, 247, 261, 256 ActionDest: 159 Annotation: Subtype: Link Rect: 544, 247, 556, 256 ActionDest: 159 Annotation: Subtype: Link Rect: 194, 209, 206, 218 ActionDest: 159 Annotation: Subtype: Link Rect: 207, 209, 219, 218 ActionDest: 159 Annotation: Subtype: Link Rect: 219, 209, 231, 218 ActionDest: 159 Annotation: Subtype: Link Rect: 419, 197, 431, 206 ActionDest: 159 Annotation: Subtype: Link Rect: 432, 197, 444, 206 ActionDest: 159 Annotation: Subtype: Link Rect: 190, 172, 202, 181 ActionDest: 159 Annotation: Subtype: Link Rect: 202, 172, 214, 181 ActionDest: 159 Annotation: Subtype: Link Rect: 206, 159, 213, 168 ActionDest: 149 Annotation: Subtype: Link Rect: 214, 159, 226, 168 ActionDest: 149 Annotation: Subtype: Link Rect: 226, 159, 238, 168 ActionDest: 156 Annotation: Subtype: Link Rect: 239, 159, 251, 168 ActionDest: 163 Annotation: Subtype: Link Rect: 251, 159, 263, 168 ActionDest: 163 Page: Sequence: 3 Annotations: Annotation: Subtype: Link Rect: 522, 609, 529, 618 ActionDest: 149 Annotation: Subtype: Link Rect: 529, 609, 541, 618 ActionDest: 163 Annotation: Subtype: Link Rect: 544, 609, 556, 618 ActionDest: 163 Annotation: Subtype: Link Rect: 266, 597, 273, 605 ActionDest: 149 Annotation: Subtype: Link Rect: 465, 596, 477, 605 ActionDest: 163 Annotation: Subtype: Link Rect: 477, 596, 489, 605 ActionDest: 163 Annotation: Subtype: Link Rect: 519, 596, 530, 605 ActionDest: 156 Annotation: Subtype: Link Rect: 531, 596, 543, 605 ActionDest: 163 Annotation: Subtype: Link Rect: 543, 596, 555, 605 ActionDest: 163 Annotation: Subtype: Link Rect: 188, 584, 200, 593 ActionDest: 163 Annotation: Subtype: Link Rect: 265, 584, 277, 593 ActionDest: 163 Annotation: Subtype: Link Rect: 330, 584, 342, 593 ActionDest: 163 Annotation: Subtype: Link Rect: 342, 584, 354, 593 ActionDest: 163 Annotation: Subtype: Link Rect: 491, 571, 503, 580 ActionDest: 163 Annotation: Subtype: Link Rect: 504, 571, 516, 580 ActionDest: 163 Annotation: Subtype: Link Rect: 406, 559, 418, 568 ActionDest: 163 Annotation: Subtype: Link Rect: 400, 534, 407, 543 ActionDest: 149 Annotation: Subtype: Link Rect: 407, 534, 419, 543 ActionDest: 163 Annotation: Subtype: Link Rect: 293, 521, 305, 530 ActionDest: 163 Annotation: Subtype: Link Rect: 461, 395, 472, 404 ActionDest: 156 Annotation: Subtype: Link Rect: 473, 395, 485, 404 ActionDest: 163 Annotation: Subtype: Link Rect: 314, 357, 326, 366 ActionDest: 163 Annotation: Subtype: Link Rect: 443, 332, 455, 341 ActionDest: 163 Annotation: Subtype: Link Rect: 455, 332, 467, 341 ActionDest: 163 Annotation: Subtype: Link Rect: 225, 282, 237, 291 ActionDest: 163 Annotation: Subtype: Link Rect: 436, 269, 448, 278 ActionDest: 156 Annotation: Subtype: Link Rect: 243, 244, 255, 253 ActionDest: 163 Annotation: Subtype: Link Rect: 411, 207, 423, 216 ActionDest: 163 Annotation: Subtype: Link Rect: 544, 182, 556, 191 ActionDest: 163 Annotation: Subtype: Link Rect: 229, 144, 241, 153 ActionDest: 163 Annotation: Subtype: Link Rect: 242, 144, 254, 153 ActionDest: 163 Annotation: Subtype: Link Rect: 257, 144, 269, 153 ActionDest: 163 Annotation: Subtype: Link Rect: 447, 131, 459, 140 ActionDest: 163 Annotation: Subtype: Link Rect: 518, 119, 530, 128 ActionDest: 166 Annotation: Subtype: Link Rect: 393, 94, 405, 103 ActionDest: 166 Page: Sequence: 4 Annotations: Annotation: Subtype: Link Rect: 422, 722, 434, 731 ActionDest: 163 Annotation: Subtype: Link Rect: 233, 685, 245, 694 ActionDest: 166 Annotation: Subtype: Link Rect: 389, 597, 401, 606 ActionDest: 159 Annotation: Subtype: Link Rect: 529, 559, 541, 568 ActionDest: 159 Annotation: Subtype: Link Rect: 487, 534, 499, 543 ActionDest: 159 Annotation: Subtype: Link Rect: 467, 471, 479, 480 ActionDest: 159 Annotation: Subtype: Link Rect: 480, 471, 492, 480 ActionDest: 159 Annotation: Subtype: Link Rect: 492, 471, 504, 480 ActionDest: 166 Annotation: Subtype: Link Rect: 319, 433, 331, 442 ActionDest: 159 Annotation: Subtype: Link Rect: 506, 408, 518, 417 ActionDest: 159 Annotation: Subtype: Link Rect: 471, 370, 483, 380 ActionDest: 166 Annotation: Subtype: Link Rect: 193, 345, 205, 354 ActionDest: 159 Annotation: Subtype: Link Rect: 205, 345, 217, 354 ActionDest: 159 Annotation: Subtype: Link Rect: 217, 345, 229, 354 ActionDest: 163 Annotation: Subtype: Link Rect: 230, 345, 242, 354 ActionDest: 166 Annotation: Subtype: Link Rect: 409, 333, 421, 342 ActionDest: 159 Annotation: Subtype: Link Rect: 238, 308, 250, 317 ActionDest: 166 Annotation: Subtype: Link Rect: 337, 283, 344, 292 ActionDest: 149 Annotation: Subtype: Link Rect: 344, 283, 356, 292 ActionDest: 156 Annotation: Subtype: Link Rect: 357, 283, 369, 292 ActionDest: 163 Annotation: Subtype: Link Rect: 336, 245, 348, 254 ActionDest: 159 Annotation: Subtype: Link Rect: 326, 220, 338, 229 ActionDest: 159 Annotation: Subtype: Link Rect: 365, 170, 377, 179 ActionDest: 159 Annotation: Subtype: Link Rect: 438, 132, 450, 141 ActionDest: 159 Annotation: Subtype: Link Rect: 203, 82, 215, 91 ActionDest: 159 Annotation: Subtype: Link Rect: 383, 82, 395, 91 ActionDest: 159 Annotation: Subtype: Link Rect: 531, 82, 543, 91 ActionDest: 159 Annotation: Subtype: Link Rect: 544, 82, 556, 91 ActionDest: 159 Page: Sequence: 5 Annotations: Annotation: Subtype: Link Rect: 246, 722, 258, 731 ActionDest: 166 Annotation: Subtype: Link Rect: 201, 634, 213, 643 ActionDest: 166 Annotation: Subtype: Link Rect: 530, 622, 542, 631 ActionDest: 159 Annotation: Subtype: Link Rect: 298, 584, 310, 593 ActionDest: 159 Annotation: Subtype: Link Rect: 198, 483, 210, 492 ActionDest: 166 Annotation: Subtype: Link Rect: 436, 483, 448, 492 ActionDest: 166 Annotation: Subtype: Link Rect: 406, 433, 418, 442 ActionDest: 166 Annotation: Subtype: Link Rect: 418, 433, 430, 442 ActionDest: 166 Annotation: Subtype: Link Rect: 441, 420, 453, 429 ActionDest: 159 Annotation: Subtype: Link Rect: 456, 420, 468, 429 ActionDest: 159 Annotation: Subtype: Link Rect: 469, 420, 481, 429 ActionDest: 166 Annotation: Subtype: Link Rect: 481, 420, 493, 429 ActionDest: 166 Annotation: Subtype: Link Rect: 322, 395, 334, 404 ActionDest: 166 Annotation: Subtype: Link Rect: 499, 383, 511, 392 ActionDest: 166 Annotation: Subtype: Link Rect: 305, 370, 317, 379 ActionDest: 166 Annotation: Subtype: Link Rect: 363, 358, 375, 367 ActionDest: 166 Annotation: Subtype: Link Rect: 190, 295, 202, 304 ActionDest: 166 Annotation: Subtype: Link Rect: 203, 295, 215, 304 ActionDest: 166 Annotation: Subtype: Link Rect: 544, 282, 556, 291 ActionDest: 166 Annotation: Subtype: Link Rect: 360, 257, 377, 266 ActionDest: 166 Annotation: Subtype: Link Rect: 378, 257, 395, 266 ActionDest: 166 Annotation: Subtype: Link Rect: 232, 182, 249, 191 ActionDest: 166 Annotation: Subtype: Link Rect: 539, 182, 556, 191 ActionDest: 166 Annotation: Subtype: Link Rect: 301, 131, 318, 140 ActionDest: 166 Annotation: Subtype: Link Rect: 527, 106, 539, 115 ActionDest: 159 Annotation: Subtype: Link Rect: 544, 81, 556, 90 ActionDest: 159 Page: Sequence: 6 Annotations: Annotation: Subtype: Link Rect: 357, 722, 374, 731 ActionDest: 166 Annotation: Subtype: Link Rect: 308, 710, 320, 719 ActionDest: 166 Annotation: Subtype: Link Rect: 331, 697, 343, 706 ActionDest: 159 Annotation: Subtype: Link Rect: 386, 631, 393, 643 ActionDest: 94 Annotation: Subtype: Link Rect: 530, 596, 542, 605 ActionDest: 159 Annotation: Subtype: Link Rect: 545, 596, 557, 605 ActionDest: 159 Annotation: Subtype: Link Rect: 206, 571, 218, 580 ActionDest: 156 Annotation: Subtype: Link Rect: 413, 559, 425, 568 ActionDest: 156 Annotation: Subtype: Link Rect: 426, 559, 443, 568 ActionDest: 169 Annotation: Subtype: Link Rect: 495, 546, 512, 555 ActionDest: 169 Annotation: Subtype: Link Rect: 205, 521, 222, 530 ActionDest: 169 Annotation: Subtype: Link Rect: 368, 521, 385, 530 ActionDest: 169 Annotation: Subtype: Link Rect: 267, 508, 284, 518 ActionDest: 169 Page: Sequence: 7 Annotations: Annotation: Subtype: Link Rect: 311, 707, 318, 716 ActionDest: 149 Annotation: Subtype: Link Rect: 319, 707, 330, 716 ActionDest: 159 Annotation: Subtype: Link Rect: 334, 707, 345, 716 ActionDest: 159 Annotation: Subtype: Link Rect: 346, 707, 358, 716 ActionDest: 159 Annotation: Subtype: Link Rect: 204, 631, 221, 640 ActionDest: 169 Annotation: Subtype: Link Rect: 221, 631, 238, 640 ActionDest: 169 Annotation: Subtype: Link Rect: 236, 581, 248, 590 ActionDest: 156 Annotation: Subtype: Link Rect: 249, 581, 266, 590 ActionDest: 169 Annotation: Subtype: Link Rect: 313, 568, 330, 577 ActionDest: 169 Annotation: Subtype: Link Rect: 210, 543, 227, 552 ActionDest: 169 Annotation: Subtype: Link Rect: 190, 531, 207, 540 ActionDest: 169 Annotation: Subtype: Link Rect: 224, 518, 241, 527 ActionDest: 169 Annotation: Subtype: Link Rect: 368, 442, 385, 452 ActionDest: 169 Annotation: Subtype: Link Rect: 386, 443, 402, 452 ActionDest: 169 Annotation: Subtype: Link Rect: 459, 430, 476, 439 ActionDest: 166 Annotation: Subtype: Link Rect: 544, 430, 556, 439 ActionDest: 159 Annotation: Subtype: Link Rect: 335, 392, 352, 401 ActionDest: 169 Annotation: Subtype: Link Rect: 521, 392, 538, 401 ActionDest: 169 Annotation: Subtype: Link Rect: 538, 392, 555, 401 ActionDest: 169 Annotation: Subtype: Link Rect: 447, 342, 464, 351 ActionDest: 169 Annotation: Subtype: Link Rect: 467, 342, 484, 351 ActionDest: 169 Annotation: Subtype: Link Rect: 248, 317, 265, 326 ActionDest: 169 Annotation: Subtype: Link Rect: 212, 304, 229, 313 ActionDest: 169 Annotation: Subtype: Link Rect: 346, 292, 362, 301 ActionDest: 169 Annotation: Subtype: Link Rect: 363, 292, 380, 301 ActionDest: 169 Annotation: Subtype: Link Rect: 210, 267, 227, 276 ActionDest: 169 Annotation: Subtype: Link Rect: 227, 267, 244, 276 ActionDest: 169 Annotation: Subtype: Link Rect: 188, 254, 205, 263 ActionDest: 169 Annotation: Subtype: Link Rect: 266, 179, 283, 188 ActionDest: 169 Annotation: Subtype: Link Rect: 284, 179, 301, 188 ActionDest: 172 Annotation: Subtype: Link Rect: 495, 166, 512, 175 ActionDest: 169 Annotation: Subtype: Link Rect: 530, 153, 547, 163 ActionDest: 172 Annotation: Subtype: Link Rect: 207, 128, 219, 137 ActionDest: 159 Annotation: Subtype: Link Rect: 220, 128, 232, 137 ActionDest: 159 Annotation: Subtype: Link Rect: 232, 128, 244, 137 ActionDest: 166 Annotation: Subtype: Link Rect: 254, 91, 271, 100 ActionDest: 172 Page: Sequence: 8 Annotations: Annotation: Subtype: Link Rect: 309, 707, 321, 716 ActionDest: 166 Annotation: Subtype: Link Rect: 324, 707, 336, 716 ActionDest: 166 Annotation: Subtype: Link Rect: 337, 707, 354, 716 ActionDest: 166 Annotation: Subtype: Link Rect: 374, 694, 391, 703 ActionDest: 172 Annotation: Subtype: Link Rect: 463, 656, 480, 666 ActionDest: 172 Annotation: Subtype: Link Rect: 480, 656, 497, 666 ActionDest: 172 Annotation: Subtype: Link Rect: 331, 631, 348, 640 ActionDest: 172 Annotation: Subtype: Link Rect: 339, 619, 356, 628 ActionDest: 172 Annotation: Subtype: Link Rect: 304, 566, 311, 578 ActionDest: 123 Page: Sequence: 9 Annotations: Annotation: Subtype: Link Rect: 407, 364, 444, 375 Annotation: Subtype: Link Rect: 299, 329, 336, 340 Annotation: Subtype: Link Rect: 469, 306, 507, 317 Annotation: Subtype: Link Rect: 513, 306, 549, 317 Annotation: Subtype: Link Rect: 467, 284, 505, 294 Annotation: Subtype: Link Rect: 511, 284, 547, 294 Annotation: Subtype: Link Rect: 95, 261, 133, 271 Annotation: Subtype: Link Rect: 139, 261, 175, 271 Annotation: Subtype: Link Rect: 127, 238, 164, 248 Annotation: Subtype: Link Rect: 359, 215, 396, 225 Annotation: Subtype: Link Rect: 402, 215, 438, 225 Annotation: Subtype: Link Rect: 182, 192, 218, 202 Annotation: Subtype: Link Rect: 205, 157, 243, 168 Annotation: Subtype: Link Rect: 438, 133, 475, 144 Annotation: Subtype: Link Rect: 59, 100, 97, 110 Annotation: Subtype: Link Rect: 503, 76, 540, 87 Page: Sequence: 10 Annotations: Annotation: Subtype: Link Rect: 292, 722, 329, 732 Annotation: Subtype: Link Rect: 335, 722, 371, 732 Annotation: Subtype: Link Rect: 177, 699, 214, 709 Annotation: Subtype: Link Rect: 95, 664, 131, 674 Annotation: Subtype: Link Rect: 189, 641, 227, 651 Annotation: Subtype: Link Rect: 240, 618, 278, 628 Annotation: Subtype: Link Rect: 284, 618, 320, 628 Annotation: Subtype: Link Rect: 295, 594, 332, 605 Annotation: Subtype: Link Rect: 256, 561, 293, 571 Annotation: Subtype: Link Rect: 299, 561, 335, 571 Annotation: Subtype: Link Rect: 387, 537, 425, 548 Annotation: Subtype: Link Rect: 247, 503, 285, 513 Annotation: Subtype: Link Rect: 291, 503, 327, 513 Annotation: Subtype: Link Rect: 310, 469, 348, 479 Annotation: Subtype: Link Rect: 172, 423, 209, 433 Annotation: Subtype: Link Rect: 216, 423, 252, 433 Annotation: Subtype: Link Rect: 291, 399, 328, 410 Annotation: Subtype: Link Rect: 368, 376, 406, 387 Annotation: Subtype: Link Rect: 445, 353, 482, 364 Annotation: Subtype: Link Rect: 441, 318, 477, 329 Annotation: Subtype: Link Rect: 145, 285, 182, 295 Annotation: Subtype: Link Rect: 189, 250, 226, 260 Annotation: Subtype: Link Rect: 208, 226, 245, 237 Annotation: Subtype: Link Rect: 214, 192, 252, 203 Annotation: Subtype: Link Rect: 59, 169, 97, 180 Annotation: Subtype: Link Rect: 140, 135, 178, 145 Annotation: Subtype: Link Rect: 184, 135, 220, 145 Annotation: Subtype: Link Rect: 459, 111, 497, 122 Annotation: Subtype: Link Rect: 95, 89, 133, 99 Page: Sequence: 11 Annotations: Annotation: Subtype: Link Rect: 59, 710, 97, 720 Annotation: Subtype: Link Rect: 425, 675, 463, 686 Annotation: Subtype: Link Rect: 469, 675, 505, 686 Annotation: Subtype: Link Rect: 517, 652, 555, 663 Annotation: Subtype: Link Rect: 131, 618, 169, 628 Annotation: Subtype: Link Rect: 230, 595, 268, 605 Annotation: Subtype: Link Rect: 274, 595, 310, 605 Annotation: Subtype: Link Rect: 166, 560, 203, 571 Annotation: Subtype: Link Rect: 135, 526, 172, 536 Annotation: Subtype: Link Rect: 197, 491, 235, 502 Annotation: Subtype: Link Rect: 206, 456, 244, 467 Annotation: Subtype: Link Rect: 250, 456, 286, 467 Annotation: Subtype: Link Rect: 434, 422, 472, 433 Annotation: Subtype: Link Rect: 478, 422, 514, 433 Annotation: Subtype: Link Rect: 145, 388, 182, 398 Annotation: Subtype: Link Rect: 188, 388, 224, 398 Annotation: Subtype: Link Rect: 520, 364, 557, 375 Annotation: Subtype: Link Rect: 59, 354, 95, 364 Annotation: Subtype: Link Rect: 502, 330, 540, 341 Annotation: Subtype: Link Rect: 175, 295, 212, 306 Annotation: Subtype: Link Rect: 218, 262, 255, 272 Annotation: Subtype: Link Rect: 498, 238, 535, 249 Annotation: Subtype: Link Rect: 387, 215, 425, 226 Annotation: Subtype: Link Rect: 253, 192, 290, 203 Annotation: Subtype: Link Rect: 296, 192, 332, 203 Annotation: Subtype: Link Rect: 404, 169, 442, 180 Annotation: Subtype: Link Rect: 448, 169, 484, 180 Annotation: Subtype: Link Rect: 416, 146, 454, 157 Annotation: Subtype: Link Rect: 460, 146, 496, 157 Annotation: Subtype: Link Rect: 59, 112, 97, 122 Annotation: Subtype: Link Rect: 59, 77, 97, 88 Page: Sequence: 12 Annotations: Annotation: Subtype: Link Rect: 104, 710, 142, 720 Annotation: Subtype: Link Rect: 482, 686, 519, 697 Annotation: Subtype: Link Rect: 240, 652, 278, 663 Annotation: Subtype: Link Rect: 284, 652, 320, 663 Annotation: Subtype: Link Rect: 292, 617, 330, 628 Annotation: Subtype: Link Rect: 336, 617, 372, 628 Annotation: Subtype: Link Rect: 431, 594, 469, 605 Annotation: Subtype: Link Rect: 59, 561, 97, 571 Annotation: Subtype: Link Rect: 103, 561, 139, 571 Annotation: Subtype: Link Rect: 462, 537, 499, 548 Annotation: Subtype: Link Rect: 320, 514, 358, 525 Annotation: Subtype: Link Rect: 364, 514, 400, 525 Annotation: Subtype: Link Rect: 421, 491, 459, 502 Annotation: Subtype: Link Rect: 404, 456, 442, 467 Annotation: Subtype: Link Rect: 143, 434, 181, 444 Annotation: Subtype: Link Rect: 187, 434, 223, 444 Annotation: Subtype: Link Rect: 187, 354, 224, 364 Annotation: Subtype: Link Rect: 276, 330, 314, 341 Annotation: Subtype: Link Rect: 320, 330, 356, 341 Annotation: Subtype: Link Rect: 441, 307, 478, 318 Annotation: Subtype: Link Rect: 479, 284, 515, 295 Annotation: Subtype: Link Rect: 521, 284, 557, 295 Annotation: Subtype: Link Rect: 297, 261, 334, 272 Annotation: Subtype: Link Rect: 341, 261, 377, 272 Annotation: Subtype: Link Rect: 396, 226, 434, 237 Annotation: Subtype: Link Rect: 440, 226, 476, 237 Annotation: Subtype: Link Rect: 520, 203, 557, 214 Annotation: Subtype: Link Rect: 479, 180, 516, 191 Annotation: Subtype: Link Rect: 521, 180, 557, 191 Annotation: Subtype: Link Rect: 59, 146, 97, 157 Annotation: Subtype: Link Rect: 95, 123, 133, 134 Annotation: Subtype: Link Rect: 139, 123, 175, 134 Annotation: Subtype: Link Rect: 59, 89, 97, 99 Annotation: Subtype: Link Rect: 113, 66, 150, 76 Annotation: Subtype: Link Rect: 157, 66, 193, 76 Page: Sequence: 13 Annotations: Annotation: Subtype: Link Rect: 233, 709, 271, 720 Annotation: Subtype: Link Rect: 277, 709, 313, 720 Annotation: Subtype: Link Rect: 113, 676, 150, 686 Annotation: Subtype: Link Rect: 157, 676, 193, 686 Annotation: Subtype: Link Rect: 104, 641, 141, 651 Annotation: Subtype: Link Rect: 95, 607, 133, 617 Annotation: Subtype: Link Rect: 59, 584, 97, 594 Annotation: Subtype: Link Rect: 103, 584, 139, 594 Annotation: Subtype: Link Rect: 59, 549, 97, 559 Annotation: Subtype: Link Rect: 427, 525, 464, 536 Annotation: Subtype: Link Rect: 470, 525, 507, 536 Annotation: Subtype: Link Rect: 118, 492, 155, 502 Annotation: Subtype: Link Rect: 413, 468, 450, 479 Annotation: Subtype: Link Rect: 104, 434, 141, 444 Annotation: Subtype: Link Rect: 118, 400, 155, 410 Annotation: Subtype: Link Rect: 118, 365, 155, 375 Annotation: Subtype: Link Rect: 59, 331, 97, 341 Annotation: Subtype: Link Rect: 161, 307, 199, 318 Annotation: Subtype: Link Rect: 205, 307, 241, 318 Annotation: Subtype: Link Rect: 519, 284, 557, 295 Annotation: Subtype: Link Rect: 59, 273, 95, 283 Annotation: Subtype: Link Rect: 467, 249, 504, 260 Annotation: Subtype: Link Rect: 306, 226, 343, 237 Annotation: Subtype: Link Rect: 350, 226, 386, 237 Annotation: Subtype: Link Rect: 519, 203, 557, 214 Annotation: Subtype: Link Rect: 59, 192, 95, 203 Annotation: Subtype: Link Rect: 338, 169, 375, 180 Annotation: Subtype: Link Rect: 205, 134, 242, 145 Annotation: Subtype: Link Rect: 469, 111, 507, 122 Annotation: Subtype: Link Rect: 513, 111, 549, 122 Annotation: Subtype: Link Rect: 448, 88, 486, 99 Annotation: Subtype: Link Rect: 492, 88, 528, 99 Annotation: Subtype: Link Rect: 436, 65, 473, 76 Page: Sequence: 14 Annotations: Annotation: Subtype: Link Rect: 256, 710, 294, 720 Annotation: Subtype: Link Rect: 194, 686, 231, 697 Annotation: Subtype: Link Rect: 237, 686, 273, 697 Annotation: Subtype: Link Rect: 356, 652, 393, 663 Annotation: Subtype: Link Rect: 288, 618, 326, 628 Annotation: Subtype: Link Rect: 353, 583, 390, 594 Annotation: Subtype: Link Rect: 396, 583, 432, 594 Annotation: Subtype: Link Rect: 454, 548, 491, 559 Annotation: Subtype: Link Rect: 424, 514, 461, 525 Annotation: Subtype: Link Rect: 321, 480, 358, 490 Annotation: Subtype: Link Rect: 349, 445, 386, 456 Annotation: Subtype: Link Rect: 440, 410, 478, 421 Annotation: Subtype: Link Rect: 484, 410, 520, 421 Annotation: Subtype: Link Rect: 437, 376, 475, 387 Annotation: Subtype: Link Rect: 481, 376, 517, 387 Annotation: Subtype: Link Rect: 271, 342, 309, 352 Annotation: Subtype: Link Rect: 513, 330, 551, 341 Annotation: Subtype: Link Rect: 186, 295, 223, 306 Annotation: Subtype: Link Rect: 229, 295, 265, 306 Annotation: Subtype: Link Rect: 181, 273, 219, 283 Annotation: Subtype: Link Rect: 225, 273, 261, 283 Annotation: Subtype: Link Rect: 496, 249, 534, 260 Annotation: Subtype: Link Rect: 519, 226, 557, 237 Annotation: Subtype: Link Rect: 59, 215, 95, 226 Annotation: Subtype: Link Rect: 462, 192, 500, 203 Annotation: Subtype: Link Rect: 91, 158, 128, 168 Annotation: Subtype: Link Rect: 414, 134, 451, 145 Annotation: Subtype: Link Rect: 222, 100, 259, 111 Annotation: Subtype: Link Rect: 266, 100, 302, 111 Annotation: Subtype: Link Rect: 337, 65, 374, 76 Annotation: Subtype: Link Rect: 381, 65, 417, 76 Page: Sequence: 15 Annotations: Annotation: Subtype: Link Rect: 140, 710, 178, 720 Annotation: Subtype: Link Rect: 184, 710, 220, 720 Annotation: Subtype: Link Rect: 387, 687, 425, 697 Annotation: Subtype: Link Rect: 470, 663, 508, 674 Annotation: Subtype: Link Rect: 312, 640, 350, 651 Annotation: Subtype: Link Rect: 356, 640, 392, 651 Annotation: Subtype: Link Rect: 220, 618, 257, 628 Annotation: Subtype: Link Rect: 264, 618, 300, 628 Annotation: Subtype: Link Rect: 217, 595, 254, 605 Annotation: Subtype: Link Rect: 353, 572, 391, 582 Annotation: Subtype: Link Rect: 397, 572, 433, 582 Annotation: Subtype: Link Rect: 398, 548, 435, 559 Annotation: Subtype: Link Rect: 442, 548, 478, 559 Checksum: d6572bd1 Type: CRC32 Checksum: a9b8d5b50fda357d4f3cce86ba4ab6f8 Type: MD5 Checksum: 385818e871d8251aa9852eb73ac8f9249d961043 Type: SHA-1