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Bulletin of the World Health Organization, 81 5. Sexually transmitted infections, 79 4. The American journal of tropical medicine and hygiene, 68 2. The Lancet infectious diseases, 3 8. Brugha, R ; Antiretroviral treatment in developing countries: the peril of neglecting private providers. Journal of medicinal chemistry, 46 3. Coast, J ; Smith, R ; Antimicrobial resistance: cost and containment. Expert review of anti-infective therapy, 1 2. The Journal of steroid biochemistry and molecular biology, 86 Health technology assessment Winchester, England , 7 The Journal of infectious diseases, 8. Acta tropica, 88 1. European journal of clinical nutrition, 57 4. Clinical and experimental immunology, 3. International journal of technology assessment in health care, 19 1. Journal of neurology, neurosurgery, and psychiatry, 74 8. The Lancet infectious diseases, 3 3. The Cochrane database of systematic reviews 4. 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Walker, D ; Economic analysis of tuberculosis diagnostic tests in disease control: how can it be modelled and what additional information is needed? Health policy and planning, 16 1. Health technology assessment Winchester, England , 5 Warhurst, D ; New developments: chloroquine-resistance in Plasmodium falciparum. Drug resistance updates, 4 3. Warhurst, DC ; A molecular marker for chloroquine-resistant falciparum malaria. The New England journal of medicine, 4. Statistics in medicine, 20 Journal of medicinal chemistry, 44 Zlotkin, S ; Arthur, P ; Antwi, KY ; Yeung, G ; Treatment of anemia with microencapsulated ferrous fumarate plus ascorbic acid supplied as sprinkles to complementary weaning foods. The American journal of clinical nutrition, 74 6. Jump to: Atom RSS.

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How can I buy cocaine online in Schaan

Official websites use. Share sensitive information only on official, secure websites. Address correspondence to: Dr. Box , Tempe, AZ E-mail: janet. Dopamine D3 receptor D3R -selective compounds may be useful medications for cocaine dependence. We investigated their effects 0, 3, 5. Both compounds were also examined for effects on locomotion and yawning induced by a D3R agonist. OS decreased cocaine and sucrose reinforcement rates, increased latency to first response for cocaine but not sucrose, and downshifted the cocaine self-administration dose-response function. WW-III did not affect cocaine self-administration on the multiple-variable interval schedule, but it reduced cocaine and sucrose intake on the progressive ratio schedule. Therefore, both compounds blocked a D3R-mediated behavior. However, OS was more effective in reducing cocaine self-administration. These findings support D3Rs, and possibly D2Rs, as targets for medications aimed at reducing the motivation to seek cocaine. The dopamine D3 receptor D3R subtype is a target for developing novel therapeutic agents for the treatment of psychostimulant addiction Levant, ; Luedtkea and Mach, ; Joyce and Millan, ; Le Foll et al. One unique attribute of the D3R is that its level of expression is much higher in the mesolimbic pathway than in other dopaminergic pathways Bouthenet et al. Other evidence implicating the D3R in psychostimulant addiction includes the findings that D3R expression is upregulated in response to the administration of several drugs of abuse Spangler et al. For instance, Mash and colleagues Staley and Mash, ; Segal et al. Furthermore, D3Rs are upregulated after cocaine self-administration in rodents, and the magnitude of that elevation appears to be related to measures of motivation to seek cocaine Neisewander et al. One challenge facing the development of D3R-selective compounds is the high degree of amino acid sequence homology between the D3R and the dopamine D2 receptor D2R Sokoloff et al. Nonetheless, several compounds with varying degrees of D3R selectivity have been identified. These D3R compounds decrease psychostimulant self-administration Xi et al. We previously reported on the development of a series of arylamide phenylpiperazines that have high affinity for D3Rs, moderate D3R:D2R binding selectivity i. Although the response rate under sucrose reinforcement was also reduced, the latency to respond i. It has been proposed that the selective increase in response latency for cocaine reflects a decrease in the motivation to seek cocaine Olmstead et al. To examine further the structure-activity relationship of arylamide phenylpiperazines in modulating cocaine self-administration, two novel arylamide phenylpiperazines, OS and WW-III, were evaluated. Competition curves were performed to determine the affinity of these compounds at dopamine D2 and D3 receptors. We then examined the ability of these two novel compounds to suppress response and reinforcement rates on a multiple variable-interval second VI second schedule of cocaine or sucrose reinforcement. The multiple VI schedule allowed us to compare directly responding under cocaine versus sucrose reinforcement within a session. Furthermore, reinforcement rates under this schedule may be less affected by drug-induced motor impairment compared with ratio schedules because there is a low response demand to obtain a reinforcer after a variable but, on average, second period on the VI second schedule. Therefore, we further examined its effect on self-administration of different doses of cocaine. Because WW-III failed to affect cocaine self-administration on the multiple VI second schedule, a subsequent experiment was conducted to examine its effects on responding for cocaine or sucrose under a progressive ratio PR schedule of reinforcement, which has a higher response requirement compared with the multiple schedule. The effects of both compounds on locomotor activity were also evaluated. For competition experiments, the radioligand concentration was generally equal to the K d value, and the concentration of the competitive inhibitor ranged over 5 orders of magnitude. The protein concentration of the membranes was determined using a bicinchoninic acid reagent Pierce, Rockford, IL and bovine serum albumin as the protein standard. Since transfected cells expressing receptor were used for this study, competition curves were modeled for a single site using eq. IC 50 values were converted to equilibrium dissociation constants K i values Cheng and Prusoff, using 0. Whole-cell cAMP accumulation was measured by an adaptation of the method of Shimizu and co-workers Shimizu et al. The media were replaced with serum-free media containing 0. Individual samples were corrected for column recovery by monitoring the recovery of the cAMP using spectrophotometric analysis at optical density nm. OS and WW-III were injected 5 minutes before the start of the test session, based on our previous study showing that arylamide phenylpiperazines attenuated l -DOPA-induced dyskinesia Kumar et al. Catheters were implanted into the jugular veins of rats participating in the cocaine self-administration experiments. Rats weighed — g at the time of surgery. Joseph, MO as described by Kufahl et al. The catheters were tunneled subcutaneously along the neck, exited through an incision across the top of the head, and secured to the top of the skull using dental acrylic and anchor screws. To maintain catheter patency, a 0. Catheter patency was tested periodically by infusing 0. Rats were given a minimum of 6 recovery days, during which they were handled briefly to administer the heparin-ticarcillin solution. Albans, VT in three sequential phases: a sucrose-only phase, a cocaine-only phase, and a multiple-schedule phase. For the OS experiment, catheter implantation surgery was performed before the sucrose-only phase. In the WW-III experiment, surgery took place after the sucrose-only phase to decrease attrition from catheter failure. In the OS experiment, the catheters of three subjects became nonpatent, giving a final number of nine subjects. In the sucrose- and cocaine-only phases, daily sessions lasted 2 hours or until the rat had earned 50 reinforcers, whichever occurred first. During the sucrose-only phase, rats were trained with sucrose pellets 45 mg; Bio-Serv, Frenchtown, NJ as the reinforcer. The right lever was the active lever. There was a cue light above the active lever to signal reinforcer availability. The left lever was inactive. Pressing the active lever once after a variable interval produced the following consequences: 1 delivery of sucrose pellet, 2 retraction of both levers, 3 offset of the cue light, and 4 onset of a tone Hz, 10 db above background for 6 seconds. The house light turned on with the offset of the tone and remained on for the next 24 seconds to signal a time-out in the OS experiment. After the time-out, the stimuli were reset: 1 the levers were reinserted, 2 the cue light above the active lever was illuminated, and 3 the house light was turned off. Therefore, in the OS experiment, the levers were retracted after each reinforcer delivery for a second time-out initially, which was subsequently increased to a second time-out. Initially, the schedule of reinforcement progressed within daily sessions from fixed-ratio 1 FR1 , to variable-interval second VI second , to VI second, and then finally to VI second. The schedule was advanced during the session if the rat received five reinforcers within 40 minutes. Once the rat had ended the session on the VI second schedule for three consecutive sessions, the VI second schedule was in effect exclusively thereafter. Rats were then given food ad libitum for the remainder of the experiment. All rats had reached ad libitum food by the 10th training session. Training in the sucrose-only phase continued until a stability criterion had been met. For the WW-III experiment, sucrose training under a VI second schedule resumed after recovery from surgery, until the 3-day stability criterion was met again. Training then progressed to the cocaine-only phase, which occurred over sessions 13 to 14 in the OS experiment and sessions 14—17 in the WW-III experiment. In the cocaine-only phase, rats were trained with cocaine 0. Once the 3-day stability criterion was met, training progressed to the multiple-schedule phase, which occurred over sessions 19—29 in the OS experiment and sessions 20—30 in the WW-III experiment. The multiple schedule consisted of eight minute components and a 1-minute time-out between components. The reinforcer available during each component alternated between sucrose and cocaine. The schedule contingency used in each component was the same as that used during the sucrose- and cocaine-only phases. Therefore, during a sucrose component, the right lever was active and the cue light above it was turned on. During a cocaine component, the left lever was active and the cue light above it was turned on. Reinforcement was delivered using a VI second schedule for all components. The cocaine dose was reduced to 0. During the 1-minute time-out between components, both levers were retracted and all lights were turned off. The reinforcer available in the first component of each session was varied randomly between sessions. Testing of OS or WW-III started after seven or more training sessions on the multiple schedule and once the 3-day stability criterion was met for both reinforcers. Each dose was tested once for each subject. The order in which doses were given was counterbalanced between rats. Test sessions were identical to the training sessions, with the exception that test sessions were shortened to four minute components with alternating reinforcers, resulting in a total test session length of 1 hour and 4 minutes. The reinforcer available during the first component sucrose or cocaine was counterbalanced within subject across test sessions. Between test sessions, rats were maintained under the multiple schedule used during training. The 3-day stability criterion was implemented between tests. After recovery from catheter implantation surgery, rats were trained to self-administer cocaine 0. The same training regimen and contingency as used in the cocaine-only phase were implemented. After a minimum of six training sessions on the VI second schedule, a series of test days was initiated, provided the 3-day stability criterion had been met. The dose of cocaine available intravenously during the 1-hour test session was increased across test days in the following order: 0, 0. Treatment order was counterbalanced between rats. Pretreatments were given intraperitoneally 5 minutes before the start of the test sessions. Rats were maintained under daily 2-hour sessions at the 0. This is because the PR schedule is more sensitive to detecting the effects of D3R compounds on psychostimulant self-administration Xi et al. Training on the PR schedule began at least 9 days after the last test session on the multiple VI second schedule. Two rats were eliminated because of catheter failure, reducing the number of subjects to eight. During the PR sessions, active and inactive lever assignments remained the same as during cocaine components on the multiple VI second schedule. Cocaine 0. Ratio requirement increased exponentially as a function of the number of reinforcers earned according to the equation 5 e 0. Thus, the progression of ratio requirement was 1, 2, 4, 6, 9, 12, 15, 20, and so forth. The session ended when the rat failed to earn a reinforcer within 1 hour or when 3 hours had elapsed since the beginning of the session, whichever occurred first. Additional sessions were run between tests until the 3-day stability criterion was met. Data from the vehicle sessions were averaged. The order of treatment was counterbalanced between rats. To determine whether the effect of WW-III observed in the PR experiment was specific to cocaine self-administration, a separate cohort of 10 rats was trained and tested under a PR schedule of sucrose reinforcement. The rats were trained on a FR1 for four sessions, after which the ratio requirement increased by 1 every session until reaching FR5. The right lever was the active lever, the left lever was inactive, and each sucrose reinforcer was delivered with the same stimuli as in the previous experiments. Sessions were terminated once a rat attained 50 reinforcers. Once rats had reached the FR5, food in their home cages was progressively increased to ad libitum, which remained in effect throughout the rest of the experiment. All rats attained ad libitum food by session 14; they were then transitioned to the previously described PR schedule. Rats were trained on the PR schedule until the 3-day stability criterion was met sessions 31— They were then tested twice: once with vehicle and once with 5. The order of treatment was counterbalanced between rats, and additional sessions were given between tests to reestablish stability. Yawning tests were conducted in the activity chambers as described herein. A new cohort of 40 rats was used to test the effect of OS On test days, rats were first habituated to the locomotor activity chambers for 30 minutes. OS or its vehicle was then administered, and the rats were returned to their home cages. Five minutes later, the assigned dose of 7-OH-DPAT was administered, the rats were immediately placed in the chambers, and yawning and locomotion were measured for 30 minutes. Rats were given at least 1 day off between test sessions. The same procedure was used as described already, except five doses of 7-OH-DPAT were tested within subjects vehicle, 0. One group was pretreated with vehicle, and the other group was pretreated with 5. A video tracking system TopScan Realtime Option version 2. The same nine rats from the OS multiple-schedule experiment were used. Testing started at least 7 days after the last session of that experiment. The order of treatments was counterbalanced between rats. Each test session was 1 hour long, and rats were given 1 day off between test sessions. Test sessions lasted 1 hour. Response rate, reinforcement rate, and response latency were analyzed using repeated measures trend analyses Keppel and Wickens, ; Howell, In the multiple schedule experiment, the dose of the D3R compound was a linear trend factor. In the cocaine dose-response experiment, the dose of cocaine was a polynomial trend factor. Response latency for each reinforcer type sucrose or cocaine was defined as the latency from the insertion of levers to the first response on the active lever. In the multiple VI second schedule, the number of reinforcers and lever presses were totaled across the two components for each reinforcer type, whereas response latencies were averaged across the two components for each reinforcer type. If a rat failed to respond during a component in the multiple schedule experiment, the duration of the component 15 minutes was used as the response latency. If a rat failed to respond during a session in the cocaine dose-response experiment, the duration of the session 1 hour was used as the response latency. Note that although trend analyses are immune to violations of variance homogeneity Keppel and Wickens, , improving variance homogeneity can increase the power to detect an effect. In the case of a significant interaction, t -tests were also used to examine simple effects at each dose of the D3R compound for the multiple schedule experiment or at each dose of cocaine for the cocaine dose-response experiment. The first analysis tested the hypothesis that the effects of the D3R compounds varied, depending on whether the session began with a cocaine component, with the four components being cocaine-sucrose-cocaine-sucrose or, if it began with a sucrose component, with the four components being sucrose-cocaine-sucrose-cocaine. The second analysis tested the hypothesis that the effects of the D3R compounds differed in the first half versus the last half of the session. The details and results of these two analyses are presented in the Supplemental Data. For the yawning experiments, polynomial trend analysis was used because 7-OH-DPAT has previously been shown to have an inverted U-shape dose-response function for yawning and a U-shape dose-response function for locomotor activity Khroyan et al. Because yawning data are count data, the number of yawns was square-root transformed before statistical analysis to improve the homogeneity of variance Moyaho and Valencia, In addition, planned comparisons between vehicle and each dose of the drug were conducted for all dose-response experiments using two-tailed t -tests. The structures of the two arylamide phenylpiperazines used in this study are shown in Fig. Analyses presented in the Supplemental data section see Supplemental Figs. Therefore, data from both types of sessions were combined for all subsequent analyses unless otherwise specified. The effects of OS on the total number of reinforcers delivered across the two minute sucrose and cocaine components are shown in Fig. OS dose dependently reduced reinforcement rates, and the slope of this reduction did not differ between reinforcer types. Planned t -tests comparing the effect of each dose of OS against vehicle, for each reinforcer type Fig. The number of reinforcers A and E , active lever presses B and F , and inactive lever presses C and G were totaled across the two minute components for sucrose gray squares or cocaine black circles components. Response latency D and H was averaged between the two minute components for each reinforcer type. Note that the ordinate for response latency is on a log scale. V, Vehicle. The effects of OS on active and inactive lever presses totaled across the two components for each reinforcer type are shown in Fig. These results confirm that rats were able to discriminate between the active versus inactive lever in both sucrose and cocaine components. This finding suggests that OS dose dependently reduced active lever response rates and that the slope of this reduction did not differ between reinforcer types. Trend analysis of inactive lever responses, totaled across the two components for each reinforcer type, found no significant trends of OS or reinforcer type and no significant interaction between the two factors Fig. The effects of OS on response latency, averaged across the two components for each reinforcer type, are shown in Fig. Planned t -tests for each reinforcer type found that response latency for cocaine was increased by 5. However, response latency for sucrose was not significantly affected by any of the doses of OS Fig. The effects of WW-III on the total number of reinforcers delivered across the two minute sucrose and cocaine components are shown in Fig. The effects of WW-III on active and inactive lever presses totaled across the two components for each reinforcer type are shown in Fig. This finding suggests that WW-III caused a mild reduction of active lever response rate across doses. Trend analysis of inactive lever responses, totaled across the two components for each reinforcer type, found no significant trends of WW-III or reinforcer type and no significant interaction between the two factors Fig. The effects of WW-III on response latency, averaged across the two components for each reinforcer type, are shown in Fig. Planned t -tests comparing response latencies at each dose of WW-III against vehicle also found no significant effects. We conducted a further analysis to examine whether the effects of OS and WW-III were comparable during the first versus the last half of the session. The results are presented in the Supplemental data Supplemental Figs. The effect of OS on reducing sucrose reinforcement rate and sucrose active lever response rates dissipated during the last half of the session compared with the first half. In contrast, the effect of OS on reducing cocaine self-administration did not depend on session half. These results suggest that the effects of OS were comparable between the two halves of the session for cocaine but not for sucrose. Although OS had no effect on sucrose response latency averaged over the whole session, it increased sucrose response latency in the first half of the session but not in the last half Supplemental Fig. The finding that OS increased sucrose response latency in the first half of the session is surprising because a previous study found that WC26 and WC44, which are partial and full D3R agonists, respectively, did not increase sucrose response latency in either session halves Figs. However, in that study, sucrose was always available during components 1 and 3, whereas cocaine was always available during components 2 and 4. Therefore, we examined the effect of OS on response latency at each individual component to facilitate comparisons. We treated the two factors—the dose of OS factor and the reinforcer type factor—as between-subject factors because both of these factors were counterbalanced between subjects within a component. Trend analysis found that, similar to WC26 and WC44, OS did not increase sucrose response latency in component 1 i. This result suggests that the lack of effect of OS on sucrose response latency is not due to a ceiling effect. Additional trend analyses Supplemental Fig. For WW-III, analysis shown in the Supplemental Data revealed that WW-III had comparable effects in the first and the last half of the session, for both reinforcer types, for 1 reinforcement rate, 2 inactive lever response rate, and 3 response latency Supplemental Figs. However, WW-III reduced active lever response rate for sucrose during the first, but not last, half of the session Supplemental Fig. The effect of OS on the number of reinforcers infusions is shown in Fig. The number of reinforcers was decreased at 1. However, after OS pretreatment, the number of reinforcers was increased only at 0. Additional t -tests examining the effect of OS at each dose of cocaine found that OS reduced the number of cocaine infusions at 0, 0. OS did not increase the number of cocaine infusions relative to vehicle pretreatment at any of the cocaine doses. Available cocaine doses were tested in an ascending dose order, whereas the order of vehicle and OS pretreatment were counterbalanced between rats. Additional stabilization sessions were given between tests. OS also reduced cocaine intake Fig. This result suggests that cocaine intake increased as a function of cocaine dose after both pretreatments. The t -tests examining the effect of OS at each dose of cocaine found that OS reduced cocaine intake at 0. OS did not increase cocaine intake compared with vehicle pretreatment at any of the cocaine doses. OS also reduced active lever response rate Fig. Active lever response rate was decreased at 1. Additional t -tests examining the effect of OS at each dose of cocaine found that OS reduced the active lever response rate at 0, 0. OS did not significantly affect the inactive lever response rate Supplemental Fig. Trend analysis and t -tests found no significant effect of cocaine dose or OS OS increased latency to the first response see Supplemental Fig. Response latency data were averaged across cocaine doses because there were no cues signaling the upcoming cocaine dose at the beginning of the test sessions. Additional tests found that final ratio achieved was reduced by pretreatment with 5. The effects of 5. The effects of OS and cocaine on locomotor activity are shown in Fig. These findings suggest that OS decreased locomotion to the same degree regardless of pretreatment with cocaine versus saline, and cocaine increased locomotion to the same degree regardless of pretreatment with OS versus vehicle. Test order was randomized with 1 day off between test sessions. Planned t -tests comparing locomotor activity at each dose of WW-III against vehicle found that 5. Both are partial agonists according to the adenylyl cyclase assay. WW-III is thus one of the most D3R-selective compounds reported in the literature, which makes it particularly useful for examining the effect of selective D3R partial activation. OS reduced cocaine self-administration in the multiple schedule. OS also reduced responding for sucrose and locomotor activity; therefore, it could be argued that OS reduced cocaine self-administration by impairing general motoric function. However, since OS increased response latency for cocaine but not for sucrose in component 1, it is unlikely that motor impairment explains all the present findings. Instead, two lines of evidence suggest that OS may be more effective in suppressing cocaine self-administration compared with responding for sucrose. First, OS increased cocaine response latency throughout the session but increased sucrose response latency only during component 2. Second, OS reduced the cocaine reinforcement rate throughout the session, but its reduction of sucrose reinforcement rate dissipated in the last half of the session. The differential effects of OS on responding for cocaine versus sucrose suggest that motivation for cocaine is reduced. OS suppressed the intake of several doses of cocaine without increasing the intake of low or high doses of cocaine. These findings suggest that OS does not potentiate the reinforcing effects of cocaine. However, even the moderate dose of 5. It did, however, reduce the final ratio achieved on the PR schedule. The ascending limb of the function is attenuated by D3R-selective antagonists, whereas yawning on the descending limb is increased by the D2R-selective antagonist L, Collins et al. This result may be due to their high D3R:D2R selectivity. However, it is possible that D3R antagonism blocked disinhibition of yawning as a result of D2R antagonism Collins et al. In vivo screens purported to be more selective for D2R effects, such as hypothermia Collins et al. The yawn counts in the present experiment are low compared with those of some reports Collins et al. There is evidence that food-related behavior is reduced by partial D3R activation Martelle et al. Further work is needed to clarify the role of D3Rs role in food-related behavior. OS attenuated, but failed to reverse completely, cocaine-induced hyperactivity, similar to the D3R partial agonist WC26 Cheung et al. The side effects of OS and WW-III in reducing locomotor activity may, in part, contribute to their reduction of operant responding. However, it should be emphasized that OS seemed more effective in reducing responding for cocaine than for sucrose, which suggests that OS reduced the motivation to respond for cocaine, in addition to any nonspecific suppression of behavior related to the reduction of locomotor activity. Previous studies indicated that compounds with high D3R:D2R selectivity are less effective in reducing cocaine self-administration when response effort is low Vorel et al. In contrast, compounds with lower D3R:D2R selectivity seem more effective in attenuating cocaine self-administration. One explanation for these findings is that D3Rs may play a pivotal role in the motivation to seek drug, whereas reinforcement may require concurrent activation of both D2Rs and D3Rs. To the extent that co-occupancy of D2Rs and D3Rs is required to attenuate cocaine reinforcement, such interactions may occur in the same or different neurons or may involve D2R-D3R heterodimers Maggio et al. Such compounds may be useful in a two-stage therapeutic strategy. Early during recovery, when the relapse rate is high, moderately D3R:D2R-selective partial agonists might be administered to attenuate craving and cocaine reinforcement if relapse occurs. They may also help normalize the dopaminergic system Fuchs et al. One issue that remains is whether the effects of D3R compounds observed in the present study change with repeated administration. Also, the rats used for two experiments PR schedule with cocaine and locomotor testing with OS had a more extensive cocaine history, which may affect D3R-mediated behavior Blaylock et al. OS was more effective in reducing cocaine self-administration compared with responding for sucrose in the multiple schedule. OS also reduced cocaine self-administration over a range of cocaine doses. WW-III failed to reduce cocaine intake in the multiple schedule despite doing so at a lower dose in the PR schedule. Both compounds reduced sucrose reinforcement rates and locomotor activity. Results from the yawning experiment provided evidence for D3R antagonism. Taken together, the results of the present study add to the evidence that D3R is a viable target for reducing cocaine-related behaviors Luedtkea and Mach, ; Heidbreder and Newman, ; Blaylock and Nader, The authors thank Julianna Goenaga, Colter Whillock, and Vijay Durai for expert technical assistance with this project. This article has supplemental material available at jpet. As a library, NLM provides access to scientific literature. J Pharmacol Exp Ther. Louis, Missouri R. Find articles by Timothy H C Cheung. Find articles by Amy L Loriaux. Find articles by Suzanne M Weber. Find articles by Kayla N Chandler. Find articles by Jeffrey D Lenz. Find articles by Romina F Schaan. Find articles by Robert H Mach. Find articles by Robert R Luedtke. Find articles by Janet L Neisewander. Open in a new tab. Similar articles. Add to Collections. 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