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In rats and mice buy paroxetine 30 mg on-line, unchanged drug accounts for up to 90% of the urinary recovery cheap 10mg paroxetine amex, which represents about 80% of the dose; the remaining urinary products consist of five metabolites discount 40mg paroxetine overnight delivery, which have been identified paroxetine 40mg lowest price. The serious adverse effects of treatment with zidovudine order paroxetine 40mg without prescription, reported in a small proportion of people, include haematotoxicity (anaemia, neutropenia), hepatotoxicity and cardiac and skeletal myopathy (due to mitochondrial effects). Studies in mice, rats and rabbits given zidovudine transplacentally showed no increase in the frequency of malformations, but some studies showed increased numbers of fetal resorptions and decreased fetal weights after oral administration of zidovudine at doses of 200–500 mg/kg bw per day during gestation. Studies in monkeys and rats indicated that the behavioural alterations in offspring exposed to zidovudine in utero were generally reversible. It produces clastogenic effects in cultured human cells and in mice exposed to either high or clinically relevant concentrations. Analyses of mutations induced in human cells in culture and in skin tumours from transplacentally treated mice showed that exposure to zidovudine also causes point mutations. There is sufficient evidence in experimental animals for the carcinogenicity of zidovudine. Retroviruses, 6, 219–228 British Medical Association/Royal Pharmaceutical Society of Great Britain (1998) British National Formulary, No. Phosphorylated 3′- amino-3′-deoxythymidine and 5′-amino-5′-deoxythymidine and derivatives. Although many studies were conducted on its use in various combinations, several large clinical trials (Bartlett et al. Zalcitabine has cross-resistance with didanosine (Roche Laboratories, 1998), which is generally more effective. The patients were recruited during 1990–91 and were followed up for a median of 1. Six cases of non-Hodgkin lymphoma were seen in the zalci- tabine-treated group and three in the didanosine-treated group. For the purposes of evaluating cancer risk, therefore, the numbers of participants were too small and the length of follow-up too short, cancer incidence may have been underascertained, and cancer rates could not be analysed adequately. Studies of Cancer in Experimental Animals Oral administration Mouse Groups of 10 male and 10 female B6C3F1 mice, six weeks of age, were treated with zalcitabine (purity, > 99%) in a 0. An additional group of 10 female mice received 1000 mg/kg bw per day for 13 weeks and were then maintained without further treatment for a one-month recovery period before termination. The unexpected finding of thymic lymphomas in one female that received the low dose and one female that received the high dose prompted the authors to conduct an additional study (Sanders et al. Groups of 70 female B6C3F1 mice, six weeks of age, were treated with zalcitabine (purity, > 99%) in a 0. The remaining 50 mice per group were held without treatment for an additional three months before termination (recovery group). Thymic lymphomas were found in 2/19 mice that received the low dose and were necropsied at the end of the 13-week exposure period, and in 3/50 and 15/50 mice at the low and high doses, respectively, that were necropsied during or at the end of the three-month recovery period. Groups of 50 male and 50 female B6C3F1 mice, six weeks of age, were treated with zalcitabine (purity > 99%) in a 0. An additional group at the high dose was treated for three months and killed six months after the start of the experiment (recovery group). There were no treatment-associated deaths among male mice, but marked treatment-associated and lymphoma-associated mortality was seen in female mice receiving the high dose and in the recovery group. The incidences of thymic lymphoma were 0%, 14%, 20% and 12% in males and 0%, 2%, 44% and 39% in females in these groups [effective numbers not reported for either sex], respectively. The thymic lymphomas involved other lymphoid organs, such as spleen and lymph nodes. Thymic atrophy was the commonest non-neoplastic lesion in treated mice, the incidences being 0%, 2%, 18% and 0% in males in the control, low-dose, high-dose and recovery groups and 0%, 12%, 20% and 0% in females in these groups, respectively. The recovery group had a lower incidence of thymic atrophy than mice at the high dose, indicating that cessation of treatment resulted in reversal of thymic atrophy (Rao et al. An additional group at the high dose (recovery group) was treated for three months. A treatment-related increase in mortality rate was seen in both males and females, with rates of 2%, 10%, 24% and 4% in males in the control, low-dose, high-dose and recovery groups and 0%, 14%, 50% and 46% in females in these groups, respectively. The deaths were due to thymic lymphomas in the females, whereas the male mice died from toxic effects of zalcitabine, such as anaemia. The incidences of thymic lymphoma were 0%, 15%, 55% and 47% in males in the control, low-dose, high-dose and recovery groups and 0%, 44%, 87% and 90% [effective numbers not reported for either sex] for females in these groups, respectively. Thymic atrophy was the commonest non-neoplastic lesion in treated mice, with incidences of 4%, 19%, 26% and 6% in males in the control, low-dose, high-dose and recovery groups and 0%, 2%, 10% and 2% in females in these groups, respectively. Both males and females in the recovery group had a lower incidence of thymic atrophy than those given the high dose conti- nuously, indicating that cessation of treatment resulted in reversal of thymic atrophy (Rao et al. This dose range is much lower than the 400- and 600-mg daily doses of didanosine and zidovudine, respectively, but the antiviral potency of zalcitabine in cell cultures is much greater than that of these other drugs. Zalcitabine is well absorbed when administered orally, with a bioavailability of the order of 80% (Klecker et al. About 75% of an oral dose is excreted unchanged in the urine, and measurable levels have been found in plasma and cerebrospinal fluid. The peak concentration of zalcitabine in cerebrospinal fluid 2 h after dosing has been reported to be 14% of that in plasma (Klecker et al.

We are unable to assess the effects of coercion or the ultimate consequences of prolonged confinement in a deprived environment cheap 10 mg paroxetine free shipping. These conditions undoubtedly have a profound effect on the motivational aspects of the situation and thus influence response buy 40 mg paroxetine with mastercard. The inability to replicate these conditions in the laboratory must limit our generalizations from the experimental data cheap paroxetine 10 mg with amex. The first experimental work which focused on the response of man exposed to reduced environmental stimulation per se was begun in 1951 in the laboratory of D discount paroxetine 30mg overnight delivery. Although earlier studies had dealt with more limited aspects of this problem quality paroxetine 10 mg, they grew out of an essentially different experimental interest. The McGill studies initially arose out of a concern with the contribution of perceptual isolation to the mechanism of brainwashing and the effects of monotony upon a person with a long sustained watchkeeping task. Previously Mackworth (52) had shown that in a vigilance task requiring prolonged observation, subjects increasingly and strikingly failed to respond to an appropriate stimulus. From this point of departure, the framework of these and other studies was expanded to focus on a wide variety of other variables. Our approach in reviewing these studies has been influenced by the consideration that in the early stages of acquiring systematic knowledge about a problem, it may be useful to underemphasize considerations of experimental rigor and elegance in favor of developing a richer background of hypotheses and conceptual formulations, even if only at a suggestive level. Because of their exploratory nature, these investigations have often been designed to look for a wide range of possible relationships, rather than to test specific, focused hypotheses. For these reasons this review will not dwell upon limitations of experimental method and procedure. In general, the studies are uneven in quality, and range from carefully designed and -58- executed procedures to vaguely formulated, poorly controlled observations with small samples. Similarly, measurement in these studies has varied from precise psychophysical calibration to loosely defined clinical judgments unchecked for reliability. The effort has been to provide a comprehensive review of all pertinent studies for whatever light they shed on the problem or support they lend other studies. In reviewing this work we have largely restricted our concern to the psychophysiological aspects of experimental work with isolation and reduced sensory input. No attempt has been made to include the social-psychological aspects of isolation which, while relevant, represent a special subproblem. For purposes of clarity we shall report the findings in the following categories: perceptual and motor abilities; cognitive and learning abilities; personality findings; feeling states; imagery; and physiology. In addition, we shall consider findings bearing on methodological choices, clinical applications, and a brief survey of theoretical interpretations. Despite some arbitrariness in these classifications and the necessity of considering the same experimental work in several categories, this approach will permit a more coherent view of the evidence within a given experimental domain. In referring to these studies, reduced patterning, imposed structuring, and homogenous stimulation are referred to as perceptual deprivation; absolute reduction in variety and intensity of sensory input will be called sensory deprivation. Perceptual and Motor Abilities The problems of vigilance under conditions of perceptual deprivation have been studied by Mackworth (52). Additional literature in this area was reviewed by Holland (44), who summarized these studies as showing a greater over-all percentage of detection when the number of signals per experimental session increases, and a more equivocal finding of an increased probability of detection for longer intersignal times. He interpreted vigilance behavior as a problem of reinforcement scheduling and probability of response. In this context, signal detections serve as reinforcements for observing responses. His own findings confirmed the earlier reports that within a given session, despite individual differences, the use of a larger number of signals increased response rate. These studies were designed to test the hypothesis that a colored Ganzfeld would lose its color under these conditions. Utilizing eyecaps made from halved table-tennis balls, these investigators found that complete disappearance of color was obtained in most cases, despite considerable individual differences in the course of the adaptation process and in the phenomenal content during adaptation. Cohen and Cadwallader (20) studied the effects of uniform visual stimulation utilizing a different apparatus. The findings showed that under both monocular and binocular conditions, subjects reported a temporary cessation of ordinary visual experience after prolonged exposure to a uniform visual field. With increased exposure to these conditions the initial reports of the field as being "foglike" changed to an experience of "blanking out. Factors that facilitated "white-out" were found to include both extensive prior stimulation and scotopic (rather than photopic) stimulation. A similar finding is reported by Ditchburn, cited by Bruner (12), who showed that if a visual pattern is stabilized on the retina so that it is not even displaced by the natural tremor of the eye, it disappears from view within about six seconds. They were told to lie on a comfortable bed in a lighted cubicle, and they wore translucent goggles, cuffs, and gloves. Upon leaving, after two or three days in the experimental situation, subjects had difficulty in focusing; objects appeared fuzzy and did not stand out from their backgrounds; the environment seemed two-dimensional; and colors appeared to be more saturated than usual. The experimenters also found deteriora- -60- tion in visual motor coordination as measured by such tasks as the Wechsler Digit Symbol test, handwriting specimens, and the copying of prose paragraphs.

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These cytoskeletal components maintain intracellular distribution of organelles and facilitate trafficking between organelles discount paroxetine 20mg amex. Motor proteins order paroxetine 20mg online, motor protein receptors generic paroxetine 10 mg with amex, or the relevant peptide sequences may be conjugated to or complexed with plasmid cheap paroxetine 40mg otc. This may result in association of plasmids with myotubules or actin filaments for more efficient transport through the cytoplasm to regions bordering the nucleus discount 10mg paroxetine with visa. The nucleus is a dynamic structure, which disassembles at the onset of mitosis and reassembles during telophase. The major barrier between the cytosolic and nucleoplasmic compartments is the hydrophobic double-bilayered barrier of the nuclear envelope. These sequences generally contain a high proportion of the basic amino acids lysine and arginine. There is often a proline residue to break a-helix formation upstream of the basic residues. This section discusses biological opportunities for systemic, cancer and pulmonary gene therapy, as well as genetic vaccines. The systemic route allows non-invasive access to many target cells that are not accessible otherwise by direct administration. Systemic gene delivery can broadly be categorized as passive and active targeting. Active targeting refers to an alteration in the natural disposition pattern of plasmids by means of target-specific ligands, which can bind specifically to receptors on the surface of target cells. Passive targeting is an attractive approach for delivery and expression of therapeutic genes to normal endothelia of lung and liver, various phagocytic cells, and potentially disseminated tumors and metastases. Following intravenous injection of plasmid/lipid complexes, gene expression was detected in various organs, with high expression in the lung. The liver is the site of many essential metabolic and secretory functions and thus also constitutes an important target for gene therapy. Potential therapies include the treatment of inherited hepatic metabolic and infectious disorders, such as hyperlipidemia, phenylketonuria, familial hypercholesterolemia, organic acidemia, urea cycle disorders, hepatitis, cirrhosis and hemophilia. Prolonged retention of gene medicines in the blood circulation might be beneficial for passive distribution of genes to both the intravascular spaces and the highly vascularized tissues, such as tumors. Even without the use of sterically stabilized liposomes, passive targeting may still be possible for gene delivery to certain tumors. Endothelial cells, hepatocytes, tumor and blood cells may be able to process both soluble macromolecules and particulate materials via receptor-mediated endocytosis. Hepatocytes represent an attractive target for the treatment of many hepatic disorders; and the potential of utilizing normal hepatocytes for the secretion of therapeutic proteins. Effective hepatocyte gene therapy requires particulate systems with the appropriate size (<100 nm in diameter) and colloidal properties, for extravasation through the sinusoidal hepatic endothelium and access to the Space of Disse, while avoiding non-specific uptake into numerous non-target sites. The receptor-binding ligand on the surface of the formulated plasmid must also compete with endogenous ligands for cell binding and internalization, and must avoid masking by adsorbed serum proteins. Incorporation of hepatocyte-specific promoter that contains binding sites for hepatocyte transcription factors within plasmid constructs may allow long duration and high levels of tissue-specific gene expression. Evidence of hepatocyte cell-specific gene expression in vivo has been obtained with the use of hepatocyte-specific promoters. However, prolonged gene expression required partial (66%) hepatectomy 15 minutes before intravenous injection of the complex into rats, probably due to stimulation of liver cell regeneration. Hepatocyte-specific gene expression has been shown using synthetic peptide-based gene delivery. Several approaches of cancer gene therapy are currently being investigated: • enhancing cellular and humoral immune responses to tumors; • inserting genes into tumor cells to evoke “cell suicide”; • modifying tumor suppressor genes or anti-oncogenes. Cytokine genes Several cytokine genes have been found to reduce tumors by stimulating localized inflammatory and/or immune responses. Upregulation of the immune system The immune system has the ability to react very strongly to foreign histocompatability antigens, even ones that have not been seen before. This property of the immune system has been utilized to generate immune responses against tumors. This may also facilitate the presentation of tumor-specific antigens to the immune system, and help the development of tumor-specific immunity. Tumor suppressor genes Tumor suppressor genes actively repress cell growth and their loss leads to tumor development. Introduction of the wild-type p53 gene in a colon cancer xenograft model has been shown to induce tumor regression due to apoptosis. Lung cancer cells are frequently deficient in p53 and are susceptible to the induction of apoptosis by overexpressed p53, making this tumor particularly suitable for gene therapy by p53. Systemic administration of the tumor suppressor gene p53 complexed with cationic liposomes significantly reduced tumor growth and metastases of nude mice injected with cancer cells. The pulmonary endothelium may act as a bioreactor for the production and secretion of therapeutic proteins, such as clotting factors and erythropoietin into the blood circulation. There is a potential benefit for acquired lung diseases, as well as cancers, to be controlled and possibly treated by expression of cytokines, surfactant, antioxidant enzymes, or mucoproteins within lung cells.

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The min- (1) Enzymes of animal order 30 mg paroxetine free shipping, plant order paroxetine 40mg overnight delivery, or mi- imum milkfat content is 50 percent by crobial origin may be declared as "en- weight of the solids and the maximum zymes"; and moisture content is 42 percent by (2) The dairy ingredients may be de- weight purchase 20mg paroxetine with amex, as determined by the methods clared cheap paroxetine 20mg amex, in descending order of predomi- described in §133 30mg paroxetine visa. The dairy ingredi- nance, by the use of the terms "milkfat ents used may be pasteurized. Gorgon- and nonfat milk" or "nonfat milk and zola cheese is at least 90 days old. The mass is cut into set forth in paragraph (a)(2) of this sec- smaller portions and allowed to stand tion, or by any other procedure which for a time. The mixed curd and whey is produces a finished cheese having the placed into forms permitting further same physical and chemical properties. While being placed in forms, The maximum moisture content is 52 spores of the mold Penicillium roque- percent by weight, as determined by fortii are added. When (2) The dairy ingredients are sub- sufficiently drained, the shaped curd is jected to the action of a lactic acid- removed from the forms and salted producing bacterial culture. Perforations are opment of acidity is continued until then made in the shaped curd and it is the dairy ingredients coagulate to a held at a temperature of approximately semisolid mass. The mass is stirred and 50 °F at 90 to 95 percent relative humid- heated until a temperature of about 145 ity, until the characteristic mold °F is reached, and is held at that tem- growth has developed. The the surface of the cheese may be whey is drained off and the curd re- scraped to remove surface growth of moved and placed in forms and pressed. One or The shaped curd is placed in whey and more of the other optional ingredients heated for 3 or 4 hours, and may again specified in paragraph (b)(3) of this sec- be pressed. It is then stored under con- tion may be added during the proce- ditions suitable for curing. Each of the in- used: gredients used in the food shall be de- (1) Dairy ingredients. Milk, nonfat clared on the label as required by the milk, or cream, as defined in §133. If the dairy ingredients used bined, is not more than six times the are not pasteurized, the cheese is cured weight of the benzoyl peroxide used. If at a temperature of not less than 35 °F the dairy ingredients are bleached in for at least 60 days. The name of the with hydrogen peroxide/catalase, and is food is "gorgonzola cheese". One or gredients used in the food shall be de- more of the clotting enzymes specified clared on the label as required by the in paragraph (b)(2) of this section is applicable sections of parts 101 and 130 added to set the dairy ingredients to a of this chapter, except that: semisolid mass. The mass is so cut, (1) Enzymes of animal, plant, or mi- stirred, and heated with continued stir- crobial origin may be declared as "en- ring, as to promote and regulate the zymes"; and separation of whey and curd. The curd is clared, in descending order of predomi- then alternately stirred and drained to nance, by the use of the terms "milkfat prevent matting and to remove whey and nonfat milk" or "nonfat milk and from curd. The following ard of identity prescribed for granular safe and suitable ingredients may be cheese by §133. All (iv) Antimycotic agents, the cumu- cheese ingredients used are either lative levels of which shall not exceed made from pasteurized milk or held at a temperature of not less than 35 °F for current good manufacturing practice, at least 60 days. Moisture may be re- may be added to the surface of the moved from the cheese ingredients in cheese. One or more sufficient quantity of catalase prepara- of the optional ingredients specified in tion to eliminate the hydrogen per- paragraph (c) of this section may be oxide. The name of the used, the minimum milkfat content of food is "granular cheese" or, alter- the food is not more than 1 percent natively, "stirred curd cheese". Each of the in- the standard of identity for that gredients used in the food shall be de- cheese. The name of in letters not more than twice as high the food shall be accompanied by a dec- as the letters in the phrase "with other laration of the specific variety of grated cheese(s)". Sufficient rennet, (4) An acidifying agent consisting of rennet paste, extract of rennet paste, one or more of the acid-reacting ingre- or other safe and suitable milk-clot- dients named in §133. The full name cium chloride in a quantity not more of the food shall appear on the prin- than 0. Wher- of the milk) is added to set the milk to ever any word or statement empha- a semisolid mass. The mass is cut pears on the label (other than in an in- into small particles, stirred, and heat- gredient statement as specified in ed. The curd is separated from the paragraph (e) of this section) so con- whey, drained, shaped into forms, spicuously as to be easily seen under pressed, salted, and cured. The rind customary conditions of purchase, the may be colored or rubbed with vege- full name of the food shall immediately table oil or both. A harmless prepara- and conspicuously precede or follow tion of enzymes of animal or plant ori- such word or statement in type of at gin capable of aiding in the curing or least the same size as the type used in development of flavor of hard grating such word or statement. One or more of the name of such hard grating cheese, if clotting enzymes specified in para- any such name has become generally graph (b)(2) of this section is added to recognized therefor; or set the dairy ingredients to a semisolid (2) If no such specific common or usual name has become generally rec- mass. The mass is cut into particles ognized therefor, an arbitrary or fan- similar in size to wheat kernels. For ciful name that is not false or mis- about 30 minutes the particles are al- leading in any particular.

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However discount 30 mg paroxetine, other techniques of administration generic 30 mg paroxetine visa, including transdermal buy paroxetine 30mg on-line, transmucosal via oral and intranasal generic 40mg paroxetine amex, epidural discount paroxetine 40 mg line, and intrathe- cal applications are well documented. Older neonates with a gestational age of at least 34 weeks may require a slightly higher mean dose of 0. Tolerance can develop rapidly, resulting in dose requirements as high as 20µg/kg/h. In older infants to children of 12 years of age, sedation with analgesia is achieved with fentanyl doses of 1 to 2µg/kg/dose I. The dose may be repeated at 30-minute intervals until the required effect is obtained. If continuous sedation is necessary, an infusion dose of 1 to 3µg/kg/h can be initiated after the initial bolus. Transdermal fentanyl can be used in children at least 2 years of age and receiving at least 45 to 60 mg of oral morphine equivalents per day. An initial transdermal patch of 25µg/h is supplemented with intermittent short acting opioids. For continuous sedation/analgesia, an infusion initiated at 1 to 2µg/kg/h can be titrated for appropriate effects. Pharmacokinetics Absorption: transmucosal absorption is rapid and followed by slow gastrointestinal tract absorption Effect (analgesia) onset: almost immediate (I. After transdermal application, the maximum analgesic effect is achieved at 24 hours compared with 20 to 30 minutes with transmucosal administration 12. Sedative Hypnotic and Anesthetic Agents 305 Duration of effect: duration of effect is dependent on the route of administration with I. In neonates to 14 years of age, the volume of distribution is reportedly greater, with a range of 5 to 30 L/kg Metabolism: fentanyl is almost exclusively metabolized in the liver to norfentanyl, hydroxyproprionyl-fentanyl, and hydroxyproprionyl- norfentanyl. In adults, fentanyl at 5 and 10µg/kg does not result in significant changes in cardiovascular param- eters. At a higher dose of 20µg/kg, significant reduction of heart rate and mean arterial blood pressure has been reported. When additional fentanyl is administered at doses up to 50µg/kg, no further heart rate or arterial blood pressure changes are observed. High doses of fentanyl can cause marked muscle rigid- ity, which may make ventilation difficult. Others Fentanyl can also cause nausea, vomiting, constipation, xerostomia, weakness, miosis, and diaphoresis. These inhibitors include azole antifungals, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, telithromycin, and verapamil ● With monamine oxidase inhibitors, a severe and unpredictable potentiation of opioid analgesics has been reported Poisoning Information Symptoms are similar to other opioid overdose and include apnea, chest wall rigidity, seizures, hypoxemia, hypotension, and bradycardia. Compatible Diluents Fentanyl is stable with the following diluents: sterile water injection, 5% dex- trose injection, and 0. Sedative Hypnotic and Anesthetic Agents 307 Midazolam Indications Midazolam has the anxiolytic, hypnotic, anticonvulsant, muscle relaxant, and antegrade amnestic effects characteristic of benzodiazepines. Lower doses of mida- zolam should be used if other opioids or sedatives are used concurrently. The dose adjustment is particularly important with opioids to avoid respiratory depression and hypotension Sedation in mechanically ventilated neonates: 0. An initial dose of 1µg/kg/min is appropriate for neonates older than 32 weeks gestational age. Individual response to midazolam can vary and, therefore, may require further titration for desired effect Pharmacokinetics Absorption: via oral and nasal route is rapid secondary to high lipophilicity Bioavailability: oral bioavailability is 15 to 45%; rectal bioavailability is 40 to 50%; intranasal bioavailability is 60% Onset of action: high lipophilicity at physiological pH results in rapid onset of activity. Onset of action is within 20 minutes when administered orally, and within 5 minutes when administered I. Metabolites include 1-hydroxymidazolam (the principal metabolite), 4-hydroxymidazolam, and 1,4-dihydroxymidazolam. The 1- and 4-hydroxy metabolites have pharmacological activity, although less than that of the parent compound Elimination: excretion occurs through urine as glucuronide-conjugated metabolites (80%) and feces (2–10%) Systemic and Adverse Effects Cardiovascular In adults, midazolam administered at 0. Sedative Hypnotic and Anesthetic Agents 309 systemic vascular resistance may decrease 15 to 33%. In healthy volunteers, tidal volumes decreased but respiratory rates increased, resulting in unchanged minute ventilation. In patients with chronic obstructive pulmonary disease, midazolam produced a more profound and longer-lasting respiratory depression than it did in healthy patients. Apnea is more likely to occur after midazolam is administered to patients premedicated with opioids. Other Other adverse effects include nausea, vomiting, nystagmus, cough, physical and psychological dependence with prolonged use, and paradoxical reaction. Poisoning Information Midazolam has been associated with respiratory depression and respiratory arrest.

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