FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2029606923> ?p ?o ?g. }

• W2029606923 endingPage "643" @default.
• W2029606923 startingPage "633" @default.
• W2029606923 abstract "Introduction The potential consequences of progressive HIV-1 infection include the development of potentially lethal opportunistic infections and malignancies, as well as progressive neurological disease, wasting and hematopoietic abnormalities, including anemia and neutropenia. Although the administration of highly active antiretroviral therapy often results, at least temporarily, in the apparent sustained suppression of viral replication, failure of therapy remains all too common. Furthermore, such therapy has not achieved virological cure, even in those patients in whom HIV RNA remains undetectable in the plasma for prolonged periods of time [1-6]. This failure of eradication is the consequence of the persistence of replication-competent virus within cellular reservoirs, which include memory T cells and macrophages [1,2,5]. Profound dysregulation of the cytokine network is at the epicenter of HIV pathogenesis [7]. For example, the production of IL-2 is impaired early in infection, whereas TNF-a levels in the serum become increased later in the course of the illness [8]. One cytokine whose role in HIV disease has been less well defined is granulocyte-macrophage colony-stimulating factor (GM-CSF), a hematopoietic growth factor whose effects extend well beyond that of its colony-stimulating activity. This 127 amino acid monomeric glycoprotein plays an important role in the development and maintenance of cellular immune responses, and may also reduce the infectivity of macrophages by HIV-1. The administration of recombinant human GM-CSF is effective in the management of neutropenia in patients with AIDS [9-11]. The ability of GM-CSF to augment host defenses against opportunistic pathogens and against HIV itself, as well as its ability to interfere with HIV infection of macrophages, suggests the potential for additional therapeutic roles for this recombinant molecule. GM-CSF cellular immunity and pulmonary homeostasis Cellular sources Activated T and B lymphocytes are the major cellular sources of GM-CSF production, but macrophages, eosinophils, endothelial cells, fibroblasts, osteoblasts, bone marrow stromal cells, blast cells, keratinocytes, thymic epithelial cells, mesothelial and uroepithelial cells, mast cells and human tracheal epithelial cells may also contribute [12,13]. Whereas production of this cytokine is minimal under basal conditions, its gene is under the transcriptional regulation of multiple promoter and enhancer elements, including nuclear factor kappa B (NF-kB) and nuclear factor of activated T cells (NF-AT), and stimulation of relevant cells by the appropriate inductive signal leads to its upregulation [14]. Monocyte to macrophage differentiation is associated with a significant increase in GM-CSF production [15]. Cellular targets GM-CSF is usually not detectable in the plasma of HIV-infected subjects or of normal controls but acts in an autocrine and paracrine fashion upon target cells expressing its cognate heterodimer receptor [8]. Cells expressing this receptor include not only granulocyte-macrophage progenitor cells, but also mature neutrophils, eosinophils, monocytes and macrophages. The engagement of GM-CSF with its receptor triggers a signalling cascade involving tyrosine phosphorylation of Janus kinase 2 (JAK2), signal transduction and activator of transcription 5 (STAT5) and, transiently, STAT3 [16-19]. This sequence of events leads to profound changes in the state of activation and function of the target cells. Role in pulmonary homeostasis Studies involving knockout mice (GM-CSF-/-) indicate that, whereas GM-CSF is not necessary for the maintenance of normal hematopoiesis, it is necessary for normal pulmonary homeostasis [20]. The lungs of GM-CSF-/- mice exhibit prominent peribronchovascular lymphocytic infiltration and, because of an inability to clear pulmonary surfactant, have alveoli filled with eosinophilic material and large macrophages [20-23]. These mice also have frequent pulmonary and soft tissue infections caused both by bacteria and fungi and have a shortened survival. Effects on T cell function and numbers GM-CSF-/- mice also have significant abnormalities of T cell function, as evidenced by diminished CD4 lymphocyte proliferative responses and T cell help for IgG production, as well as the impaired development of cytotoxic CD8 lymphocyte response [24]. These functional abnormalities appear to be the result, at least partly, of diminished T cell responsiveness to IL-2, a defect that is restored by a soluble factor produced by GM-CSF-stimulated dendritic cells. Although its cognate receptor is reportedly absent on T cells, the presence of GM-CSF receptor mRNA in these cells has been described, a finding that suggests the possibility of low-level receptor expression [25]. This observation may explain some described effects of GM-CSF on T cells. For instance, GM-CSF augments the induction of lymphokine-activated killer (LAK) cell function by low-dose IL-2 and also amplifies IL-2-induced human T cell proliferation in vitro [25-27]. The administration of GM-CSF to lymphoma patients results in an increase in CD8 and CD4 lymphocyte counts, as well as of CD25 expression and the serum concentration of sIL-R [28]. Furthermore, the administration of GM-CSF to patients after autologous bone marrow transplantation for lymphoma or multiple myeloma is associated with the accelerated recovery of CD4 T cells [29]. Effects on antigen-presenting cells GM-CSF activates normal neutrophils as well as monocytes/macrophages, leading to their differentiation and enhancement of their phagocytic and microbicidal activity. The effects of GM-CSF on mature neutrophils include the upregulation of the surface adhesion molecules, CD11b and LAM-1, enhanced phagocytosis, degranulation and priming for respiratory burst with resultant increased superoxide anion generation, increased antibody-dependent cellular cytotoxicity, and inhibition of apoptosis [30-45]. At low concentrations, GM-CSF enhances neutrophil motility, but at high concentrations, it inhibits motility, thus providing a concentration gradient effect, attracting and then maintaining these cells at sites of inflammation [43,45]. In addition, GM-CSF enhances in-vitro neutrophil cytotoxic activity against HIV-1-infected cells [46]. GM-CSF enhances superoxide anion production by normal human monocytes and neutrophils in vitro and increases their phagocytic and intracellular fungicidal activity against Candida albicans. GM-CSF also augments the killing of Candida glabrata by neutrophils and promotes the fungistatic activity of human peripheral blood mononuclear cells and rat alveolar macrophages against Cryptococcus neoformans [47-53]. The fungistatic activity of human peripheral blood monocytes against Histoplasma capsulatum is enhanced by preincubation with GM-CSF [54]. Human monocytes have antifungal activity against hyphal elements of Aspergillus fumigatus, which is comparable to that of neutrophils; this activity is enhanced by GM-CSF in vitro [55]. The administration of GM-CSF reduces the intensity of pulmonary infection with Pneumocystis carinii in CD4 lymphocyte-depleted mice [56]. The exposure of human macrophages to GM-CSF enhances their ability to restrict the intracellular growth of both Mycobacterium tuberculosis and Mycobacteriurn avium complex (MAC) organisms, and also increases the antimycobacterial activity of a variety of antimicrobials against intracellular MAC [57-60]. The administration of GM-CSF to C57BL16 beige (bg/bg) mice experimentally infected with MAC diminishes the intensity of infection and also enhances the activity of both azithromycin and amikacin in the model [60]. The administration of GM-CSF to AIDS patients with MAC bacteremia increases their monocyte superoxide production as well as their ability to restrict the intracellular growth of MAC ex vivo [61]. GM-CSF also stimulates the tumoricidal cytotoxic activity of monocytes in vitro and ex vivo after subcutaneous administration [62,63]. GM-CSF enhances antigen presentation by macrophages by, at least partly, the increased expression of Class I and Class II molecules, B-7 accessory molecules, and the C1b non-polymorphic molecule important in the presentation of non-peptide mycobacterial antigens [64]. It also increases the production by these cells of important effector molecules, such as G-CSF, IL-1 and TNF. GM-CSF modestly enhances the production of IL-12, apparently by priming for increased synthesis of the p40 subunit, by human peripheral blood monocytes, albeit to a lesser extent than does IFN-g [65,66]. Macrophages (along with CD8 lymphocytes) are the principal source of b-chemokines in the lymph nodes of HIV-infected individuals [67]. Dendritic cells, including Langerhans cells, which are derived from a monocyte/macrophage lineage, are potent antigen- presenting cells and are also a source of IL-12 and may thus play a role in T-helper (Th) cell type 1 development [68,69]. GM-CSF, together with IL-4, causes in-vitro differentiation and maturation of dendritic cells from human CD14 peripheral blood monocytes. Immature dendritic cells express mRNA for the chemokine receptors CXCR4, CCR5, both of which are functionally expressed at the cell surface, and CCR3, which is not [70]. The GM-CSF-induced maturation of dendritic cells is associated with downregulation of the b-chemokine receptors, presumably resulting in the inhibition of infection with R5 strains of HIV-1; CXCR4, however, persists and remains functional, responding to its cognate ligand, SDF-1. Freshly isolated epidermal Langerhans cells express functional CCR5, but not CCR4, whereas cultured Langerhans cells, as well as dendritic cells, express both receptors [71]. GM-CSF upregulates B7-1 and B7-2 on Langerhans cells in vitro [72,73]. IFN-g suppresses B7-1 expression by Langerhans cells; this suppression is partly reversed by GM-CSF [74]. Whereas one group of investigators [75] has reported that GM-CSF does not cause b-chemokine production by macrophage-derived monocytes (MDM) in the absence of CD40L, another group [76] has reported contrary results. The latter investigators [76] found that supernatant fluids from monocytes as well as MDM that had been stimulated by GM-CSF contained high concentrations of MIP-1a and MIP-1b, and that these supernatants inhibit the infection of a CCR5-expressing cell line by an R5 strain of HIV-1 (Fig. 1). The discrepancy in results between the two groups appears to be the result of differing experimental conditions, particularly the timing of exposure to GM-CSF.Fig. 1: GM-CSF stimulates peripheral blood monocytes and monocyte-derived macrophages to secrete large amounts of MIP-1a and MIP-1b, thus inhibiting the infection by HIV-1 of cells expressing CCR5 [76]. The infection of CCR5-expressing CD4 cells may also be potentially prevented.Microglial cells are the resident macrophages of the central nervous system [77]. Exposure of developing murine microglial cells to GM-CSF causes them to acquire accessory cell function for both Th1 and Th2 cells [78]. Because recombinant GM-CSF crosses the blood-brain barrier, it may play a role in immune defense within the central nervous system [79]. The ability of GM-CSF to enhance antigen presentation has led to examinations of its potential utility as a vaccine adjuvant. Studies in animal models have demonstrated its potent adjuvancy, either when co-administered with antigen as recombinant GM-CSF or as produced in vivo by transfected cells, in antitumor and anti-HIV-l vaccines [80-85]. Macrophages, HIV infection and GM-CSF Macrophages represent an important target of HIV infection in vivo and play a critical role in the pathophysiology of this disease. These cells are believed to be the means by which HIV reaches the central nervous system, where they or their progeny play a key role in the development of HIV encephalopathy. Dysfunction of these cells plays an important role in the impaired host response to many opportunistic infections and malignancies as well as to HIV itself. Finally, HIV-infected macrophages may serve as a reservoir that resists viral eradication and cure by antiretroviral therapy. Whereas freshly obtained peripheral blood monocytes are relatively impermissive to infection with HIV, in-vitro differentiation of these cells to a macrophage phenotype leads to increased susceptibility to viral entry, despite the greater expression of CD4 on fresh than mature cells [86-88]. Although infection may be productive, it is non-cytopathic. As a consequence, these cells may be persistent sources of viral production and may play a dominant role in this process in late-stage CD4 T cell-depleted patients [89,90]. Macrophages are the probable source of HIV-1 infection of the central nervous system, an important anatomical reservoir of infection [5]. Microglial cells, which are derived from macrophages, are the major site of HIV replication, as well as the probable source of associated neurotoxin production within the central nervous system [91]. Many contradictory results with regard to the function of macrophages in HIV-infected patients have been published. These disparate results appear to be caused by differing methodologies and subject selection. It is likely, for instance, that the stage of disease and the viral load affect the function of these cells. Nonetheless, the bulk of the evidence suggests that macrophage function is impaired, especially with regard to antigen presentation, in HIV disease. MDM of HIV-infected individuals exhibit a reduced density of B7 molecules as well as resistance to the upregulation of costimulatory molecule expression by exposure to IFN-g [92]. The number of dendritic cells is reduced in HIV-infected individuals as is their antigen-presenting function, impaired helper function in the induction of T cell proliferative responses, and impaired B cell helper function [93-96]. Immature dendritic cells can be productively infected with M-tropic HIV-1 and can serve as a source of virus that can infect activated CD4 T cells [97]. On the other hand, mature dendritic cells, as well as peripheral blood monocytes, although being infectable with M-tropic HIV-1, demonstrate a block at the level of reverse transcription resulting in a lack of viral replication. Effect of GM-CSF on HIV infection and replication in macrophages Peripheral blood monocytes infected in vitro with HIV-1 demonstrate a diminished secretion of GM-CSF and, in addition, the production of GM-CSF in vitro by CD4 lymphocytes is diminished in parallel with the progression of HIV disease [98,99]. GM-CSF has been reported both to enhance HIV-1 replication in acutely infected monocytes as well as in a chronically infected promonocytic cell line (Ul), and also to suppress its replication [100-103]. These apparently contrary results are largely the consequence of variations in patient selection and experimental conditions, especially the timing of the addition of GM-CSF to the cell culture. Treatment of the monocytic cell line, U937, with GM-CSF before acute infection led to a marked suppression of HIV-1 antigen expression [104]. GM-CSF does not affect viral replication in co-cultures of HIV-pulsed dendritic cells and CD4 T cells [105]. It should also be noted that, under conditions in which increased HIV replication has been observed, GM-CSF enhances the antiviral effect of zidovudine (ZDV) against HIV-1-infected macrophages, probably as a consequence of increased thymidine kinase activity, resulting in an increase in the concentration of azidothymidine-5‚-triphosphate [102,106-108]. The chemokine receptor CCR5 serves as co-receptor for M-tropic (R5) strains of HIV-1, without regard to viral clade, and its expression is necessary for viral infectivity by these strains [109]. CCR5 is abundantly expressed not only by tissue macrophages, but also by a subset of CD45Ro memory T cells expressing high concentrations of CD26 and CD95 [110]. CCR5, as well as CCR3, is preferentially expressed on Th1 cells, whereas Th2 cells preferentially express CCR4, with some expression of CCR3 [111]. Microglial cells express both CCR3 and CCR5; monoclonal antibody to CCR5, but not CCR3, slows viral infection and replication in these cells [112]. It has previously been reported that viral entry by HIV-1 is more efficient in macrophages than in monocytes, an observation consistent with recent findings that chemokine receptor expression is altered during monocyte differentiation [87]. Freshly obtained monocytes have a relatively abundant expression of CXCR4 and a limited expression of CCR5 (Fig. 2). Differentiation during in-vitro culture for 5 days, however, results in an increase in the proportion of cells expressing CCR5 from less than 20% to over 80%, presumably accounting for the increased ability to infect and replicate in these cells [113,114]. When, however, freshly isolated monocytes are exposed to GM-CSF for 7 days, leading to differentiation to macrophages, both CXCR4 mRNA and CCR5 mRNA (as well as CCR2b) expression are suppressed and acute infection with M-tropic HIV-1 is blocked as a result of decreased viral entry [114] (Fig. 2). Although contrary results, presumably as a consequence of different experimental conditions, have been reported, these findings are consistent with recent clinical data described below [115]. GM-CSF, presumably as a consequence of its downregulation of CCR-5 expression, thus diminishes the infectability of macrophages.Fig. 2: During in-vitro cultivation of peripheral blood monocytes, CCR5 expression is markedly increased, rendering these cells subject to infection by HIV-1. The cultivation of monocytes for 7 days in serum-containing medium, however, results in markedly decreased expression of this chemokine receptor, together with decreased infectability of these monocyte-derived macrophages by M-tropic strains of HIV-1 [114].The mechanism by which GM-CSF downregulates the expression of CCR5 on macrophages is unknown. Cell surface expression of CCR5 in individuals with the CCR5/CCR5 genotype is quite variable and presumably results, at least partly, from the potential plasticity of the regulation of its synthesis [110]. This includes a complex alternative splicing pattern as well as multiple transcription start sites resulting in transcripts with 5′-end heterogeneity, which can apparently be initiated from two distinct promoters [116]. The CCR5 gene promoters consist of two exons separated by a 1.9kb intron. CCR5 mRNA can be detected constitutively in primary human myeloid and lymphoid cells [117]. CCR5 promoter activity can by upregulated by phorbol myristate acetate (PMA), IL-2 or anti-CD3 antibody, and binding sites for a number of transcriptional factors are present. CD3-mediated upregulation of CCR5 promoter activity is markedly reduced by anti-CD28 antibody [118]. Other molecules are known to affect CCR5 expression. IFN-g increases the expression of CCR1, CCR3, and CCR5 in the monocytoid U937 cell line with concomitant enhanced HIV-1 entry [119]. Retinoic acid treatment of U937 cells also induces CCR5 expression and R5 infectivity [120]. Agents such as dibutyryl-cAMP or prostaglandin E2, which increase the intracellular concentration of cAMP, rapidly downregulate CCR5 gene expression and markedly decrease HIV-1 entry into pretreated MDM [121]. Whether GM-CSF affects the cAMP levels in macrophages has not been reported, but it does increase its concentration (as well as that of cGMP) in human T lymphocytes [25]. Whatever the mechanism, the amount of functional CCR5 expressed is critical to the infectability of macrophages by R5 strains of HIV-1. Individuals homozygous for a 32 base pair deletion in the CCR5 gene, resulting in the complete absence of a functional receptor, are highly resistant to infection with HIV-1 [122-125]. Individuals heterozygous at this allele are apparently not protected from infection but, if infected, have delayed progression of disease and a greater likelihood of being long-term non-progressors than those without this mutation. Even in the absence of allelic changes, however, the degree of CCR5 expression may vary 20-fold among individuals, presumably as a consequence of the complex pattern of splicings and dual promoter usage of its gene, a combination which causes diversity in the regulatory control of gene expression [116,126,127]. This variability may account for at least a portion of the long-term non-progressors not explained by the heterozygosity of the CCR5 gene. The relative amounts of CD4 and CCR5 expression are critical to the establishment of infectivity of macrophages because the creation of a functional fusion complex appears to require an appropriate stoichiometric expression of receptor and of co-receptor. Cells expressing large amounts of CD4 thus require only small numbers of CCR5 molecules for maximal R5 infection; in the presence of low CD4 expression, as in MDM, the high expression of CCR5 is required [128,129]. The critical nature of this quantitative relationship between CD4 and CCR5 expression provides a potential target for exploitation by novel therapeutic approaches, a variety of strategies for which have been described [130]. The blockade of CCR5 by a natural or modified ligand, or with monoclonal antibodies, impairs, with varying efficiency, the infection of macrophages with R5 strains of HIV-1 [131,132]. Aminooxypentane-RANTES (regulated upon activation: normal T cell expressed/secreted), an N-terminal modified RANTES, downmodulates surface CCR5 expression and inhibits the recycling of internalized CCR5 to the surface, with a concomitant reduction of cell entry of an R5 strain of HIV-1 [133]. As indicated above, molecules such as prostaglandin E2, which increase the intracellular concentration of cAMP, rapidly downregulate the expression of CCR5 [121]. Genetic approaches, utilizing intrakine or intrabody strategies, also have as their goals the diminished expression of this chemokine receptor. The ability of GM-CSF, readily available in recombinant form with a record of safety in HIV-infected patients, to downregulate CCR5 makes this recombinant molecule a prime candidate for investigation. This is especially true because GM-CSF has, as described above, the potential for improving cellular immunity, reducing the incidence of opportunistic infections (and, possibly, malignancies), interfering with ongoing HIV infection, and accelerating the elimination of a reservoir of infection, potentially accelerating antiretroviral cure. Some clinical trial data providing preliminary information concerning these issues have been presented. Clinical evaluation of effect of GM-CSF administration in HIV-infected subjects In a study of only 28 days‚ duration, the daily injection of GM-CSF in 12 HIV-infected patients with CD4 counts of less than 200/mm3 receiving stable ZDV therapy had no significant effect on CD4 or CD8 T cell counts or on HIV viral load as determined by culture or polymerase chain reaction (PCR) [108]. More prolonged administration has been associated with favorable results. In an open randomized trial, GM-CSF was administered, after a week of 300μg daily, at a dose of only 150μg twice a week for an additional 11 weeks to 123 leukopenic (white blood cells (WBC) <3000/mm3) HIV-infected patients with a mean CD4 cell count of 103±57/mm3; 121 controls with similar baseline characteristics were observed during the 12 week study. Despite the low dose of GM-CSF utilized, there was a sustained improvement in WBC in the active treatment group [9]. This group also evidenced an increase in both CD4 and CD8 T cell counts, although statistical significance was lost at the 24 week follow-up (12 weeks after the last dose of GM-CSF). Opportunistic infections occurred in 61.7% of the active treatment group and in 72% of controls (P=0.123). There was a statistically significant difference in the frequency of infections between the two groups at weeks 15 and 20, however, and significant differences were noted at multiple time points in each subgroup, stratified by the severity of neutropenia, including those with absolute neutrophil counts at entry of 1¥109/l or greater. There was no significant change in serum p24 antigen in this group of patients, who were largely treated with a single nucleoside reverse transcriptase inhibitor (NRTI). Bernstein and colleagues [134] have also reported an increase in CD4 count in HIV-infected GM-CSF recipients. In a placebo-controlled randomized trial [135], the administration twice a week of GM-CSF (sargramostim) for 6 months to HIV-infected patients with baseline CD4 counts of less than 300/mm3, who were receiving ZDV or ZDV plus another NRTI was associated with increased CD4 T cell counts and a reduced plasma HIV viral load. At 6 months, the median change in viral load was thus -0.01 log10 in placebo recipients and -0.51 log10 in GM-CSF recipients (P=0.02), and more individuals in the latter group (80%) had an increase in CD4 cell count of over 30% than did placebo recipients (58%; P=0.027). Conclusion In addition to its accepted role in the management of neutropenia, GM-CSF has the potential for other important therapeutic activities in HIV-infected patients. GM-CSF is necessary for the maintenance of pulmonary homeostasis, and has important effects on the cellular immune response, especially by its enhancement of antigen presentation, accessory cell function, and microbicidal and tumoricidal activity of professional phagocytes. In addition, GM-CSF has significant effects on HIV replication. By downregulating CCR5 and CXCR4 expression on macrophages, it inhibits viral infectivity of these cells by, respectively, R5 and, possibly, dual-tropic (R5XR4) strains of HIV-1 [136]. This effect, together with its stimulation of b-chemokine production by macrophages, also prevents the infection of nearby cells. The bystander cells thus protected are the subset of memory CD4 T cells, which express CCR5 and may serve as a persistent reservoir of infection. HIV-1 infection of macrophages is non-cytolytic and, with an estimated half-life of approximately 14 days, tissue macrophages are also potentially capable of acting as a long-lasting reservoir of HIV infection, especially in sites such as the central nervous system [77]. Evidence, in fact, indicates that macrophages are a major source of virus during advanced HIV disease [5]. The administration of GM-CSF has the potential to improve immune responses and to be useful in the prevention of opportunistic infections, as well as to be an effective adjunct to antiretroviral therapy. The prevention of infection of macrophages and memory CD4 T cells by GM-CSF administration could potentially play a key role in accelerating virological eradication. When administered together with highly active antiretroviral therapy, GM-CSF has the potential to reduce this long-lived cellular reservoir of HIV-1 infection, possibly reducing the risk of the emergence of drug resistance and of accelerating the achievement of viral eradication. The value of GM-CSF in non-neutropenic HIV-infected patients can, however, only be determined in controlled clinical trials, some of which are currently in progress." @default.
• W2029606923 created "2016-06-24" @default.
• W2029606923 creator A5080503866 @default.
• W2029606923 date "1999-04-01" @default.
• W2029606923 modified "2023-10-11" @default.
• W2029606923 title "Granulocyte-macrophage colony-stimulating factor: potential therapeutic, immunological and antiretroviral effects in HIV infection" @default.
• W2029606923 cites W1511309136 @default.
• W2029606923 cites W1529061070 @default.
• W2029606923 cites W1593137160 @default.
• W2029606923 cites W1620558271 @default.
• W2029606923 cites W1686460 @default.
• W2029606923 cites W1821594997 @default.
• W2029606923 cites W1830857550 @default.
• W2029606923 cites W1840516913 @default.
• W2029606923 cites W1879557309 @default.
• W2029606923 cites W1940408935 @default.
• W2029606923 cites W1964892825 @default.
• W2029606923 cites W1967643308 @default.
• W2029606923 cites W1969976495 @default.
• W2029606923 cites W1971777539 @default.
• W2029606923 cites W1976290995 @default.
• W2029606923 cites W1984811742 @default.
• W2029606923 cites W1986226400 @default.
• W2029606923 cites W1986574361 @default.
• W2029606923 cites W1987587119 @default.
• W2029606923 cites W1996054527 @default.
• W2029606923 cites W1996183144 @default.
• W2029606923 cites W1996634009 @default.
• W2029606923 cites W1997333023 @default.
• W2029606923 cites W1998990074 @default.
• W2029606923 cites W2003902256 @default.
• W2029606923 cites W2004319639 @default.
• W2029606923 cites W2011406016 @default.
• W2029606923 cites W2011850477 @default.
• W2029606923 cites W2013522291 @default.
• W2029606923 cites W2025921582 @default.
• W2029606923 cites W2026444780 @default.
• W2029606923 cites W2028002620 @default.
• W2029606923 cites W2028341833 @default.
• W2029606923 cites W2030697288 @default.
• W2029606923 cites W2032918869 @default.
• W2029606923 cites W2034186927 @default.
• W2029606923 cites W2035552180 @default.
• W2029606923 cites W2036890038 @default.
• W2029606923 cites W2037005014 @default.
• W2029606923 cites W2038048329 @default.
• W2029606923 cites W2039613763 @default.
• W2029606923 cites W2047385013 @default.
• W2029606923 cites W2049163438 @default.
• W2029606923 cites W2049504140 @default.
• W2029606923 cites W2050292538 @default.
• W2029606923 cites W2050842983 @default.
• W2029606923 cites W2051269276 @default.
• W2029606923 cites W2053006593 @default.
• W2029606923 cites W2055103634 @default.
• W2029606923 cites W2056183769 @default.
• W2029606923 cites W2057589663 @default.
• W2029606923 cites W2060435945 @default.
• W2029606923 cites W2063058638 @default.
• W2029606923 cites W2066517837 @default.
• W2029606923 cites W2068222016 @default.
• W2029606923 cites W2068595389 @default.
• W2029606923 cites W2073879459 @default.
• W2029606923 cites W2075171892 @default.
• W2029606923 cites W2077193261 @default.
• W2029606923 cites W2081190361 @default.
• W2029606923 cites W2090630729 @default.
• W2029606923 cites W2090646713 @default.
• W2029606923 cites W2102252876 @default.
• W2029606923 cites W2106774411 @default.
• W2029606923 cites W2114654929 @default.
• W2029606923 cites W2116014786 @default.
• W2029606923 cites W2117342688 @default.
• W2029606923 cites W2121738391 @default.
• W2029606923 cites W2122840398 @default.
• W2029606923 cites W2123412033 @default.
• W2029606923 cites W2123804736 @default.
• W2029606923 cites W2126255146 @default.
• W2029606923 cites W2127815795 @default.
• W2029606923 cites W2134253983 @default.
• W2029606923 cites W2138386194 @default.
• W2029606923 cites W2139250164 @default.
• W2029606923 cites W2142928758 @default.
• W2029606923 cites W2144019382 @default.
• W2029606923 cites W2145090129 @default.
• W2029606923 cites W2146084524 @default.
• W2029606923 cites W2152003330 @default.
• W2029606923 cites W2154319486 @default.
• W2029606923 cites W2156117117 @default.
• W2029606923 cites W2157418548 @default.
• W2029606923 cites W2158440928 @default.
• W2029606923 cites W2158528246 @default.
• W2029606923 cites W2164931869 @default.
• W2029606923 cites W2165627434 @default.
• W2029606923 cites W2226281711 @default.
• W2029606923 cites W2314683697 @default.
• W2029606923 cites W2316772 @default.
• W2029606923 cites W2338028093 @default.

• next