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One cause is the statistical energy and experimental simplicity afforded by managed crosses, which obviously may be attempted solely in laboratory animals hiv infection malaysia discount 400 mg zovirax overnight delivery. Starting with inbred progenitors (see below), a single set of grandparental breeders can easily beget lots of of the genetically segregating F2 hybrid or backcross mice wanted for mapping advanced traits by linkage hiv infection rate kenya buy genuine zovirax online. Simultaneous evaluation of the various existing inbred strains themselves can now even be used for gene identification by haplotype mapping hiv infection rate sri lanka cheap zovirax 800mg fast delivery. On completion of the human and mouse genome sequences, Mural and colleagues (2002) performed an in depth analysis of the genes on mouse chromosome sixteen antiviral response purchase zovirax with paypal. The evolutionarily historical role of nociception suggests that mammals must be quite related in genetic and physiological processing of this explicit organic trait, despite the very fact that humans probably have a more subtle cognitive and emotional dimension to their pain. Although any variety of rat strain differences of relevance to pain have been demonstrated (see Xu and Wiesenfeld-Hallin 2004, Fecho et al 2005, Fecho and Valtschanoff 2006, LaCroix-Fralish et al 2005, Paulson et al 2005, Avsaroglu et al 2007, Terner et al 2006, Herradon et al 2007, Rode et al 2007), the mouse has clearly turn out to be the default laboratory subject for genetic analysis. One cause is the much bigger number of commercially obtainable inbred mouse strains (Beck et al 2000) than inbred rat strains. Another is the comparatively extra dense genetic map within the mouse, which led to accomplished sequencing of the mouse genome (Waterston et al 2002) several years before that of the rat (Gibbs et al 2004). Probably crucial cause for ascendance of the mouse in ache genetics analysis was the distinctive capability in this species to create transgenic knockout mice (although rat knockouts can now be constructed; Jacob et al 2010), which triggered intense interest in the normative responses of the inbred mouse strains by which such mutations are created. Along the best way to answering these questions, one can undertake both a "bottom-up" (genotype phenotype) or a "top-down" (phenotype genotype) strategy. With a bottom-up strategy, one focuses on a specific gene (usually recognized via the identified position of its protein product in pain) and research the connection between expression of that gene and a few systems-level pain phenomenon. With a topdown strategy, one examines populations exhibiting contrasting systems-level phenotypes. The responsible genes will produce both proteins with a change or deletion of an amino acid or acids within the populations being compared or proteins which are alternatively spliced to mirror completely different exons. The numerous strategies in current use are discussed briefly; their respective advantages and downsides within the examine of pain genetics have been addressed previously (Mogil and McCarson 2000). This is merely a restatement of the elemental question of reductionist ache biology, which goals to define the molecular "players": the proteins taking half in a job in mediation of ache notion and modulation. The second kind of ache genetics asks the query, of the pain-relevant genes, which are answerable for individual differences in sensitivity to pain and analgesia and for differential susceptibility and/or expression of painful pathologies Systemsor behavioral-level neural phenomena (traits or phenotypes, represented in the determine by the brain) are produced by the coordinated activity of proteins interacting with one another and with small molecules and ions. Proteins are produced by genes in either a one-to-one method (as in genes A and D) or through various splicing by which one gene can produce a number of proteins (as in genes B and C). Not pictured are protein�protein interactions and protein�gene interactions during which proteins can have an result on the expression of their very own gene or others. Environmental elements additionally produce proteinlevel modifications, which may then affect gene expression, together with by way of epigenetic regulation. In "top-down" approaches, contrasting phenotypes are compared, and genes whose expression and/or sequence also distinction are sought. In other words, one can use top-down strategies to seek out the genes relevant to the phenotype and use bottom-up strategies to review how the genotype impacts the phenotype. Three public mutagenesis initiatives (Hrabe de Angelis et al 2000, Nolan et al 2000, Sayah et al 2000) included a nociceptive assay (hot plate test), but information describing only one pain-relevant mutant have been ever revealed (Cook et al 2007). A genome-wide screen of Drosophila mutations just lately recognized a thermal avoidance gene in flies that seems to play an analogous role in people (Neely et al 2010) (see below). When profitable, nevertheless, it has provided spectacular demonstrations of the position of particular genes in ache. Selective Breeding Selective breeding is the oldest of the top-down approaches and has been carried out in agriculture and animal husbandry for millennia. Also generally recognized as synthetic selection, the method as applied scientifically involves two-way breeding of a genetically heterogeneous stock of animals based mostly on their response in regard to a trait of interest (see Crabbe et al 1990). Only extreme responders are used to beget the following era of offspring, and the resultant "excessive" and "low" traces will start to diverge phenotypically for all heritable traits. The great benefit of the approach is that every one trait-relevant genes will ultimately become fastened in alternate allelic states within the two lines such that very sturdy phenotypic variations are demonstrated. Much has Transgenic Knockout Mice and Other Mutants By far the commonest bottom-up approach to pain genetics is the creation and testing of transgenic knockout mice. These are genetically engineered null mutants in which a single gene is effectively ablated through homologous recombination of embryonic stem cells with a transgenic concentrating on vector (see Capecchi 1989).
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The mechanism of action was unclear to these investigators, but a leukotomy-like motion and an antihistaminic impact have been suggested hiv infection rate in botswana cheap zovirax 400mg without a prescription. Taub described eventually using fluphenazine as the neuroleptic because of its better aspect impact profile antiviral immunity 800mg zovirax with visa. He noticed that this latter drug appeared to him to be the painrelieving agent in the combination hiv infection rates decreasing purchase zovirax canada. The acute pain research are few in quantity with unfavorable studies of amitriptyline, 50 and seventy five mg, and desipramine, seventy five and 225 mg, although the potentiation of morphine by desipramine and not by amitriptyline is of interest (Levine et al 1986) hiv infection by gender best order zovirax. The prevention of acute (and chronic) postmastectomy pain by venlafaxine wants corroboration. Only amitriptyline (N + S) relieved arthritic ache in comparison with desipramine (N) and trazodone (S). Fluoxetine (S) was superior to amitriptyline (S + N) in a big selection of rheumatic situations, but again, the dose of amitriptyline was solely 25 mg. In the group of "miscellaneous chronic ache disorders," there was evidence for an effect of sertraline (S) on non-cardiac chest pain, fluvoxamine (S) on prostadynia, and amitriptyline (S + N) on continual facial pain. What are we to conclude in regards to the relative efficacy of those totally different antidepressants The knowledge counsel that duloxetine is a second-line drug for chronic pain based mostly on comparative figures. These information point out that antidepressants are most likely as protected (in terms of withdrawal adverse effects) and efficient as newer medicine such because the gabapentinoids (gabapentin, pregabalin). A difference of a minimum of 30% ache reduction is considered clinically important, but 50% or greater enchancment over placebo is incessantly used. Some trials (but clearly not all), nonetheless, could have failed as a outcome of they were underpowered or the medication used had been inadequately dosed. As a results of the limited efficacy of all medicine for continual ache when used as monotherapy, mixture remedy with a quantity of drugs is often essential. It is essential to rigorously explain the goals of therapy and adverse effects to sufferers. Patients also need to know that the starting dose should be low and be increased slowly (every week or so) until satisfactory aid happens or an insupportable adverse effect is skilled. Weight achieve may occur with some agents, by which case diet and appropriate weight monitoring are important, significantly within the already obese inhabitants. Less frequent opposed results include allergic reactions corresponding to rash, tachycardia (usually supraventricular), and paradoxical insomnia. It is prudent to eliminate, if potential, all different ineffective analgesics and sedating drugs in order that drug interactions causing effects such as sedation and constipation are minimized. Useful baseline tests are blood stress measurement supine and standing, hematology, liver and kidney perform, electrolytes, and an electrocardiogram. Close follow-up (every 2 weeks initially) is necessary to oversee compliance and dose increments and to cope with opposed effects. Pre-emptive prescription of a stool softener and an artificial saliva mouth spray are helpful routine measures. Combination remedy is often reasonable and needed in refractory instances (gabapentinoids, opioids, cannabinoids, and topical agents). Adverse occasions are sometimes problematic and a few could be dealt with on a pre-emptive basis. More comparative studies 490 Section Three Pharmacology and Treatment of Pain therapy with other analgesics is commonly needed, and new medicine and approaches are needed. References Alcoff J, Jones E, Rust P, et al: Controlled trial of imipramine for chronic low again pain, Journal of Family Practice 14:841�846, 1982. Bansal D, Bhansali A, Hota D, et al: Amitriptyline vs pregabalin in painful diabetic neuropathy; a randomized, double-blind clinical trial, Diabetic Medicine 26:1019�1026, 2009. Blumer D, Zorick F, Heilbronn M, et al: Biological markers for despair in chronic pain, Journal of Nervous and Mental Disease a hundred and seventy:425�428, 1982. Effectiveness and relationship of antimigraine and antidepressant results, Neurology 26:121�127, 1976. Descombes S, Brefel-Courban C, Thalamas C, et al: Amitriptyline treatment in persistent drug-induced headache: a double blind comparative pilot study, Headache forty one:178�182, 2001. Dickens C, Jayson M, Sutton C, et al: the connection between ache and melancholy in a trial using paroxetine in victims of chronic low again ache, Psychosomatics 41:490�499, 2000. Gingras M: A clinical trial of Tofranil in rheumatic ache generally practice, Journal of International Medical Research 4(Suppl 2):41�49, 1976. Goldenberg D, Schmid C, Ruthazer R, et al: A randomized double-blind crossover trial of fluoxetine and amitriptyline in therapy of fibromyalgia, Arthritis and Rheumatism 39:1852�1859, 1996.
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Ketamine causes reminiscence deficits, reproduces with impressive accuracy the symptoms of schizophrenia, is broadly abused, and induces vacuoles in neurons at average concentrations and cell demise at greater concentrations hiv transmission method statistics cheap zovirax 200mg online. Memantine, in distinction, is properly tolerated; although cases of psychotic unwanted effects have been reported, in placebo-controlled medical research the incidence of side effects is remarkably low hiv infection sore throat order cheap zovirax. Studies using dexamethasone for postoperative ache aid have produced largely positive outcomes, especially with surgical procedures involving a considerable amount of tissue trauma, similar to orthopedic and neurological surgery (Masferrer et al 1994) rates of hiv infection are higher in __________ prisoners cheap 200mg zovirax mastercard. In a meta-analysis of perioperative dexamethasone, preoperative administration of dexamethasone produced a extra consistent analgesic impact than intraoperative administration did (De Oliveira et al 2011) hiv infection classification order zovirax 800mg amex. Acetylcholine may trigger analgesia via direct action on the M1 and M3 spinal cholinergic muscarinic receptor and nicotinic receptor subtypes and not directly via stimulation of release of the second messenger nitric oxide in the spinal wire. However, intrathecal and epidural administration of neostigmine provides effective postoperative analgesia. Its scientific use, however, is limited by important unwanted side effects, specifically, nausea, vomiting, and sedation (Kaya et al 2004, Ho et al 2005). Nicotine is a basic agonist at these receptors, and newer nicotinic compounds such as epibatidine have been studied in ache models. More particularly, the analgesic impact is believed to occur primarily by way of inhibition of reuptake of norepinephrine quite than serotonin at spinal dorsal horn synapses, with secondary activity at sodium channels (Sawynok et al 2001). This receptor system additionally exists within the mind, where its activation can produce sedation. Cardiovascular depression from 2-adrenergic agonists can occur at each mind and spinal twine sites (Eisenach and Tong 1991). These side effects of sedation and sympathetic inhibition limit using 2-adrenergic agonists to just an adjuvant position as analgesics. Clonidine binds to 2-adrenergic receptors in the central nervous system, as properly as to imidazoline receptors in the mind (Kahn et al 1999). It has been hypothesized that clonidine acts at 2adrenergic receptors in the spinal cord to stimulate the discharge of acetylcholine, which acts at each the muscarinic and nicotinic subtypes for postoperative ache reduction (Duflo et al 2005). Clonidine has been administered by varied systemic routes as an adjuvant to reduce postoperative pain: orally, intravenously, and as a transdermal patch. Since its approval for medical use, dexmedetomidine has been used for sedation throughout surgery and within the postoperative period. Dexmedetomidine is an 2-adrenergic agonist with even better selectivity for that receptor than clonidine has (Coursin et al 2007). Glucocorticoids There is a long historical past of using glucocorticoids to reduce irritation and postoperative pain in plenty of surgical procedures (Salerno and Herman 2006). Glucocorticoids (corticosteroids) are steroids that bind with excessive affinity to the glucocorticoid receptor within the cytosol of cells. There are a quantity of websites of motion at which glucocorticoid-activated receptors produce anti-inflammatory and immunosuppressive results (Fleischli and Adams 1999). However, the highly effective anti-inflammatory nature of corticosteroids, by way of inhibition of prostaglandin synthesis, may also have detrimental unwanted effects with high or repeated dosing. Dexamethasone is an artificial glucocorticoid with high potency and a long period of motion (half-life of two days), however it has no mineralocorticoid activity. For example, duloxetine is a potent, balanced inhibitor of serotonin and norepinephrine reuptake. Venlafaxine inhibits serotonin reuptake at decrease dosages and inhibits each serotonin and norepinephrine reuptake at higher dosages (Dworkin et al 2007). Several clinical trials have been carried out, but most of them have demonstrated no significant analgesic impact superior to placebo (Beaulieu 2006). However, these lessons of medicine appear to be promising in patients with continual ache. Local Anesthetics One of the primary makes use of of native anesthetics for anesthesia occurred in the late nineteenth century and concerned cocaine. The chemical construction of local anesthetics in scientific use consists of an aromatic (lipophilic) benzene ring linked to an amino group (hydrophilic) via both an ester or amide intermediate chain. The intermediate hyperlink classifies the local anesthetic as either an ester (procaine, chloroprocaine, tetracaine, and cocaine) or an amide (lidocaine, prilocaine, mepivacaine, bupivacaine, etidocaine, and ropivacaine). At peripheral nerves the reduction in sodium inflow results in a decrement in action potential formation and propagation. This is particularly essential in ambulatory or fast-track surgical procedure protocols to hasten postoperative recovery and decrease hospitalization time (Kehlet and Wilmore 2008, Buvanendran and Thillainathan 2010). Mean morphine consumption over the preliminary 24 hours was decrease within the 30 mg ketorolac group (37.
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The therapeutic trials of cannabinoids for neuropathic pain reported to date are insufficiently powered to detect such rare however significant antagonistic occasions hiv infection rates by county quality zovirax 800 mg. Furthermore, though some therapeutic trials have monitored sufferers for as a lot as 1 12 months, this can be an inadequate interval to detect the long-term opposed results of cannabinoids hiv infection symptoms signs 400 mg zovirax sale. It is unimaginable to disregard the implications of these details for cannabinoids being developed for persistent common administration in patients with long-term circumstances similar to neuropathic pain pharmacology antiviral quiz order 400 mg zovirax fast delivery. However, these data could reveal perception into the neurobiology of despair (Hill and Gorzalka 2009) hiv infection probability generic 400mg zovirax with amex. More work is necessary to find out whether or not peripherally restricted modulators of the endocannabinoid system would produce a extra circumscribed and beneficial spectrum of therapeutic efficacy in people than brain-penetrant therapeutic agents would. The exact magnitude, relevance, and implications of this danger with therapeutic cannabinoid use are at present unknown. All these targets are being keenly pursued in academia and the pharmaceutical trade. A examine of Sativex for the therapy of central ache as a result of multiple sclerosis has lately been accomplished clinicaltrials. More work is necessary to discover out whether or not adjunctive therapies that combine endocannabinoid modulators with exisiting analgesics may enhance the analgesic efficacy of accessible analgesics and cut back undesirable side-effects. References Abadji V, Lin S, Taha G, et al: (r)-Methanandamide: a chiral novel anandamide possessing greater potency and metabolic stability, Journal of Medicinal Chemistry 37:1889�1893, 1994. Agarwal N, Pacher P, Tegeder I, et al: Cannabinoids mediate analgesia largely by way of peripheral kind 1 cannabinoid receptors in nociceptors, Nature Neuroscience 10:870�879, 2007. Barth F: Cannabinoid receptor agonists and antagonists, Expert Opinion on Therapeutic Patents 8:301�313, 1998. Bisogno T, Maurelli S, Melck D, et al: Biosynthesis, uptake, and degradation of anandamide and palmitoylethanolamide in leukocytes, Journal of Biological Chemistry 272:3315�3323, 1997. Bujalska M, Tatarkiewicz J, de Cord� A, et al: Effect of cyclooxygenase and nitric oxide synthase inhibitors on streptozotocin-induced hyperalgesia in rats, Pharmacology eighty one:151�157, 2008. Calignano A, La Rana G, Giuffrida A, et al: Control of ache initiation by endogenous cannabinoids, Nature 394:277�281, 1998. Connell K, Bolton N, Olsen D, et al: Role of the basolateral nucleus of the amygdala in endocannabinoid-mediated stress-induced analgesia, Neuroscience Letters 397:180�184, 2006. De Petrocellis L, Melck D, Bisogno T, et al: Endocannabinoids and fatty acid amides in most cancers, inflammation and associated problems, Chemistry and Physics of Lipids 108:191�209, 2000. Di Forti M, Morgan C, Dazzan P, et al: High-potency cannabis and the chance of psychosis, British Journal of Psychiatry 195:488�491, 2009. Di Marzo V, Fontana A, Cadas H, et al: Formation and inactivation of endogenous cannabinoid anandamide in central neurons, Nature 372:686�691, 1994. Henquet C, Krabbendam L, Spauwen J, et al: Prospective cohort examine of cannabis use, predisposition for psychosis, and psychotic symptoms in young people, British Medical Journal 330:11, 2005. Proceedings of the Royal Society of London, Series B, Biological Sciences 265:2081�2085, 1998. Fox A, Kesingland A, Gentry C, et al: the function of central and peripheral cannabinoid1 receptors in the antihyperalgesic exercise of cannabinoids in a model of neuropathic pain, Pain 92:91�100, 2001. Galiegue S, Mary S, Marchand J, et al: Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations, European Journal of Biochemistry 232:54�61, 1995. Gallant M, Dufresne C, Gareau Y, et al: New class of potent ligands for the human peripheral cannabinoid receptor, Bioorganic & Medicinal Chemistry Letters 6:2263�2268, 1996. Gaoni Y, Mechoulam R: Isolation, construction and partial synthesis of an active constituent of hashish, Journal of the American Chemical Society 86:1946�1947, 1964. Holdcroft A, Maze M, Dore C, et al: A multicenter dose-escalation research of the analgesic and adverse effects of an oral cannabis extract (Cannador) for postoperative pain administration, Anesthesiology 104:1040�1046, 2006. Classification of cannabinoid receptors, Pharmacological Reviews fifty four:161�202, 2002. Indraccolo U, Barbieri F: Effect of palmitoylethanolamide-polydatin mixture on continual pelvic pain associated with endometriosis: preliminary observations, European Journal of Obstetrics, Gynecology, and Reproductive Biology one hundred fifty:76�79, 2010. Kouznetsova M, Kelley B, Shen M, et al: Desensitization of cannabinoidmediated presynaptic inhibition of neurotransmission between rat hippocampal neurons in tradition, Molecular Pharmacology 61:477�485, 2002. Ohno-Shosaku T, Maejima T, Kano M: Endogenous cannabinoids mediate retrograde indicators from depolarized postsynaptic neurons to presynaptic terminals, Neuron 29:729�738, 2001. LoVerme J, La Rana G, Russo R, et al: the search for the palmitoylethanolamide receptor, Life Sciences 77:1685�1698, 2005. Mackie K, Lai Y, Westenbroek R, et al: Cannabinoids activate an inwardly rectifying potassium conductance and inhibit Q-type calcium currents in AtT20 cells transfected with rat mind cannabinoid receptor, Journal of Neuroscience 15:6552�6561, 1995.
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These mechanisms may affect the output of autonomic nuclei of the mind stem and spinal twine, as well as spinal nociceptive motor reflexes hiv infection lymphocyte count generic zovirax 200 mg without a prescription. The evidence reviewed signifies that some of these mechanisms could additionally be involved within the hypnotic modulation of pain hiv infection in zambia discount 400 mg zovirax with visa. The hypnotic suggestion of analgesia induced a major increase in ache threshold in all topics hiv infection rates chicago buy zovirax with visa. In eleven subjects (subgroup 1), strong inhibition of the reflex was noticed, in keeping with the results of Kiernan and associates (1995) described earlier hiv infection rates by gender purchase zovirax uk. In the other seven topics (subgroup 2), strong facilitation of the reflex occurred. All the subjects in each subgroups displayed similar decreases within the amplitude of late somatosensory evoked cerebral potentials during hypnotic analgesia. These outcomes recommend that completely different methods of modulation may be operative during efficient hypnotic analgesia and that they depend on the subject. A decrease within the late somatosensory evoked potential occurred in all topics, in preserving with both a mechanism that serves to inhibit pain-related data from reaching the somatosensory cortex and a mechanism that serves to cut back subsequent cognitive processing of ache. The inhibition of somatosensory processing seems to narrate to inhibition at spinal levels in some subjects and maybe at higher ranges in others (in whom the spinal flexion reflex is facilitated). The results of Danzinger and colleagues (1998) partially corroborate and prolong these of Kiernan and associates (1995) by indicating the potential of two general physiological mechanisms of pain inhibition. Activation of the nociceptive system at numerous levels of the neuraxis induces numerous autonomic responses (J�nig 1995), and many psychophysiological research, together with those investigating hypnosis, assist the existence of a constructive relationship between ache notion and the autonomic response. For instance, both cardiovascular response and pain scores evoked by experimental ischemia have been shown to decrease considerably following hypnotic suggestions of analgesia (Lenox 1970). Likewise, decrease pain ratings have been associated with smaller increases in coronary heart price in hypnotized subjects uncovered to the cold pressor take a look at (Hilgard et al 1974). In the research by De Pascalis and associates (2001) described above, targeted analgesia not solely produced the strongest analgesic impact and lowered brain potential responses but in addition led to a discount within the pores and skin conductance and coronary heart price response to the electrical noxious stimuli. These results strongly help the existence of a functional interaction between ache perception and autonomic activation that could be separated from the bodily traits of the noxious stimulus. Rainville and colleagues (1999a) found that the increase in stimulus-evoked coronary heart fee was significantly correlated with the change in ache unpleasantness induced by hypnosis, unbiased of modifications in ache depth, thus suggesting a direct functional interaction between ache have an result on and autonomic activation. The speedy changes in peripheral physiological responses to noxious stimuli indicate that the central neurophysiological mechanisms engaged during hypnotic analgesia may affect the mind stem and spinal techniques answerable for autonomic regulation. In conclusion, both the psychological and neural mechanisms of hypnotic analgesia are prone to be various. They embrace factors related to reinterpretation of the meanings associated with pain and factors associated to lowered pain intensity. The latter may finish up from both dissociative mechanisms or mechanisms associated to specializing in alternative or decreased sensations. Other components relate to the endogenous circuitry that descends to the brain stem and spinal levels, inhibits nociceptive transmission throughout the cells of origin of the ascending pathways, and modulates motor and autonomic responses. Rigorous experimental methodology generates studies that use standardized hypnotic approaches, whereas the more sophisticated, individualized techniques are used extra frequently in case reviews or studies of small teams. There remains to be a necessity for rigorous analysis of the more refined hypnotic interventions, and this is extra prone to be achieved by the buildup of fine single-subject and small-group research than by randomized managed trials. Assessment of the Efficacy of Clinical Hypnotic Analgesia Montgomery and co-workers (2000) performed a metaanalysis of the consequences of hypnosis on clinical pain. Their inclusion standards were restricted to studies that used hypnosis in an attempt to scale back pain, studies that included a no-treatment or standard-treatment management group, and research that included adequate data to permit calculation of impact sizes. This strategy resulted within the inclusion of 18 studies and calculation of 27 effect sizes. Based on a mixed evaluation of greater than 900 members, the authors concluded that hypnotic interventions are an effective means of manufacturing analgesia. They discovered that hypnosis offers substantial pain reduction in 75% of the population. More recent prolonged critiques have also provided some indication that acute procedural as properly as chronic ache may profit from hypnosis (see Jensen and Patterson 2006, Stoelb et al 2009, Patterson 2010).
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