Alcohol consumption in late adolescence and early adulthood - where is the problem?

Risky single-occasion drinking (RSOD) is more common in late adolescence and early adulthood (approximately between the ages of 16 and 30) than in any other period in life. This is also the age when young people in Switzerland and many other European countries are legally allowed to buy and drink alcohol, but they usually do not yet have adult responsibilities. This paper reviews evidence from the international literature and provides examples of studies conducted in Switzerland demonstrating that (a) RSOD is by far most prevalent on Saturday evenings followed by Friday evenings, usually because young people go out and do not have any work or study responsibilities the next day; (b) RSOD results from drinking in private before going out ("predrinking") and accelerating the pace of drinking (i.e. increasing the number of drinks consumed per hour); (c) RSOD is often not accidental but purposeful,. to seek excitement, to have fun and to feel the effects of alcohol; (d) RSOD occurs predominantly outside the home, mostly in bars, pubs, discos or at special events and festivals; (e) RSOD often results in intended and unintended injuries and other acute consequences, which are leading risk factors for mortality and morbidity in this age group. Effective prevention strategies should include attempts to reduce opportunities to engage in heavy drinking as well as strategies to reduce its harmful consequences.

Dirac and reduced quantization: A Lagrangian approach and Application to Coset Spaces

A Lagrangian treatment of the quantization of first class Hamiltonian systems with constraints and Hamiltonian linear and quadratic in the momenta, respectively, is performed. The first reduce and then quantize and the first quantize and then reduce (Diracs) methods are compared. A source of ambiguities in this latter approach is pointed out and its relevance on issues concerning self-consistency and equivalence with the first reduce method is emphasized. One of the main results is the relation between the propagator obtained la Dirac and the propagator in the full space. As an application of the formalism developed, quantization on coset spaces of compact Lie groups is presented. In this case it is shown that a natural selection of a Dirac quantization allows for full self-consistency and equivalence. Finally, the specific case of the propagator on a two-dimensional sphere S2 viewed as the coset space SU(2)/U(1) is worked out. 1995 American Institute of Physics.

Alpha1b-adrenergic receptors control locomotor and rewarding effects of psychostimulants and opiates.

Drugs of abuse, such as psychostimulants and opiates, are generally considered as exerting their locomotor and rewarding effects through an increased dopaminergic transmission in the nucleus accumbens. Noradrenergic transmission may also be implicated because most psychostimulants increase norepinephrine (NE) release, and numerous studies have indicated interactions between noradrenergic and dopaminergic neurons through alpha1-adrenergic receptors. However, analysis of the effects of psychostimulants after either destruction of noradrenergic neurons or pharmacological blockade of alpha1-adrenergic receptors led to conflicting results. Here we show that the locomotor hyperactivities induced by d-amphetamine (1-3 mg/kg), cocaine (5-20 mg/kg), or morphine (5-10 mg/kg) in mice lacking the alpha1b subtype of adrenergic receptors were dramatically decreased when compared with wild-type littermates. Moreover, behavioral sensitizations induced by d-amphetamine (1-2 mg/kg), cocaine (5-15 mg/kg), or morphine (7.5 mg/kg) were also decreased in knock-out mice when compared with wild-type. Ruling out a neurological deficit in knock-out mice, both strains reacted similarly to novelty, to intraperitoneal saline, or to the administration of scopolamine (1 mg/kg), an anti-muscarinic agent. Finally, rewarding properties could not be observed in knock-out mice in an oral preference test (cocaine and morphine) and conditioned place preference (morphine) paradigm. Because catecholamine tissue levels, autoradiography of D1 and D2 dopaminergic receptors, and of dopamine reuptake sites and locomotor response to a D1 agonist showed that basal dopaminergic transmission was similar in knock-out and wild-type mice, our data indicate a critical role of alpha1b-adrenergic receptors and noradrenergic transmission in the vulnerability to addiction.

Characterising avian haemosporidian communities : ecological factors, parasite persistence and co-infection

Les parasites jouent un rôle clef dans l'évolution des comportements et des traits d'histoire de vie de leurs hôtes. Le parasitisme s'avère parfois dévastateur à l'échelle de population d'hôtes, et peut également altérer certains traits associés à la valeur sélective d'un individu infecté, tels que son succès reproducteur ou encore son taux de mortalité. La coévolution hôte/parasite, qui représente l'une des forces sélectives les plus puissantes dans l'évolution des organismes, peut également conduire les partenaires de l'association parasitaire à s'adapter localement à des environnements hétérogènes. Cette thèse porte sur l'étude de parasites aviaires, du genre Plasmodium, Haemopro- teus et Leucocytozoon (Haemosporidae), naturellement associés à différentes populations de mésanges charbonnières (Parus major) et d'hirondelles des fenêtres (Delichon ur- bicum). Dans un premier temps, nous avons cherché à déterminer comment se distribuent ces parasites au sein de différentes populations hôtes et si ces communautés de parasites sont structurées. Par la suite, la principale question à laquelle nous voulions répondre était de savoir comment ces parasites, et notamment après coexistence de plusieurs lignées génétiques d'Haemosporidae au sein dun même-individu (i.e. co-infection), affectent la physiologie et le succès de reproducteur des hôtes. Nos résultats suggèrent que la distribution des Haemosporidae est principalement gouvernée par la présence d'insectes vecteurs et que la persistance de l'infection chez les hôtes varie en fonction du genre d'Haemosporidae (Chapitre 1-2). Par ailleurs, nous avons trouvé que des lignées de parasite génétiquement distinctes peuvent avoir des effets contrastés sur leurs hôtes. Par exemple, les hôtes exhibent des différences de parasitémie marquées en fonction des lignées de parasites responsable de l'infection. De plus, le succès reproducteur ainsi que la charge parasitaire des mésanges infectées par Plasmodium ou Haemoproteus n'étaient pas affecté par l'infection simultanée avec Leucocytozoon (Chapitre 2-3). Dans le Chapitre 4, j'ai examiné la capacité immunitaire de mésanges charbonnières infectées par des hémosporidies. Les résultats n'ont pas été concluant, et je suggère fortement une réévaluation de ceux-ci dans de futures études. Les mésanges charbonnières ne semblent pas signaler leur statut infectieux par la coloration de leur plumage (Chapitre 5); toutefois, la coloration noire des plumes reflète l'état de stress oxydatif des mésanges, qui dépend lui-même de l'infection parasitaire. La coloration verte pourrait également indiquer la qualité des soins paxentaux délivrés par les mésanges adultes femelles à leurs petits, comme le suggère la corrélation que nous avons observée entre la masse des jeunes d'une nichée et la coloration de leur mère. Les hirondelles capturées en Algérie souffrent plus de l'infection que celles échantillon¬nées en Europe (Chapitre 6). Les similitudes observées entre les communautés de par¬asites affectant les populations européennes et celles des populations nord-africaines suggèrent que la transmission des parasites a lieu lors de la migration vers le sud. A l'instar de nos observations sur les mésanges dans les chapitres 2 et 3, les hirondelles co-infectées ne montrent pas d'altérations de leur condition physique. Cette thèse démontre qu'il existe, au sein des populations de mésanges charbonnières, des interactions antagonistes entre, d'une part, les parasites et leurs hôtes et d'autre part, entre différent parasites. Le résultat de ces interactions antagonistes varie en fonction des espèces et de la zone géographique considérée. Nous avons démontré que les interactions ne suivent pas toujours la théorie, puisque la coevolution qui, en suivant le concept de la virulence, devrait augmenter la charge parasitaire et diminuer la condition physique des hôtes, ne montre pourtant pas d'impact négatif sur les populations de mésanges. Nous pouvons maintenant concentrer nos efforts à la caractérisation des interactions antagonistes. De plus, grâce aux avancées des méthodes moléculaires, nous pouvons suivre et étudier en détails comment ces interactions se manifestent et quels sont leurs effets sur la condition physique des hôtes. - Parasites are key in shaping various behavioural and life-history traits of their hosts. The influence of parasitism on host populations varies from slight to devastating and might influence such parameters as mortality rates or reproductive success. Host-parasite coevolution is one of the most powerful selective forces in evolution and can lead to local adaptation of parasites and hosts in spatially structured environments. In this thesis, I studied haemosporidian parasites in different populations of great tits (Parus major) and house martins (Delichon urbicum). Firstly, I wanted to determine how parasites are distributed and if parasite communities are structured. The main question I wanted to address hereafter was how parasites, and specifically infection with multiple genera of parasites (i.e. co-infection) influenced host physiology and reproductive success. I found that parasite distribution is environmentally driven and could therefore be closely linked to vector prevalence; and that the stability of parasite infection over time is genus-dependent (Chapter 1 - 2). I further found that different haemosporidian lineages might interact differently with their hosts as parasitaemia was strongly lineage-specific and that the presence of Leucocytozoon parasites showed no correlation to Plasmodium or Haemoproteus parasitaemia, nor to great tit reproductive success (Chapter 2-3). In Chapter 4 I examined immune capacity of haemosporidian-infected great tits. The results proved inconclusive, and I strongly suggest re-evaluation hereof in future work. Great tits do not appear to signal parasite infection through plumage colouration (Chapter 5); however, infection did have a link to oxidative stress resistance which is strongly signalled through the black breast stripe, with darker males being more resistant and darker females less resistant. Females might incur different costs associated with darker stripes. This would allow reversal of signaling function. Green colouration could also serve as a cue for female provisioning quality as indicated by the strong correlation between colouration and chick body mass. Breeding house martins caught in Algeria suffer greater haemosporidian infection than European populations (Chapter 6). Similar parasite communities in European and North-African populations suggest transmission of parasites may occur during southward migration. Similarly to what was observed in great tits in Chapter 2 and 3, no relationship was found between parasite co-infection and Swiss house martin body condition. This thesis demonstrates that host-parasite and inter-parasite antagonistic interac¬tions exist in great tit populations. How these interactions play out is species dependent and varies geographically. I have demonstrated that interactions do not always follow the theory, as co-infection - which under the concept of virulence should increase parasitaemia and decrease body condition - showed no negative impact on great tit populations. We can now concentrate our efforts on characterising these antagonistic interactions, and with the advance in molecular methods, track and investigate how these interactions play out and what the effect on host fitness is.

Using register data to assess the impact of response enhancement methods on the risk of nonresponse bias and survey costs

The pursuit of high response rates to minimise the threat of nonresponse bias continues to dominate decisions about resource allocation in survey research. Yet a growing body of research has begun to question this practice. In this study, we use previously unavailable data from a new sampling frame based on population registers to assess the value of different methods designed to increase response rates on the European Social Survey in Switzerland. Using sampling data provides information about both respondents and nonrespondents, making it possible to examine how changes in response rates resulting from the use of different fieldwork methods relate to changes in the composition and representativeness of the responding sample. We compute an R-indicator to assess representativity with respect to the sampling register variables, and find little improvement in the sample composition as response rates increase. We then examine the impact of response rate increases on the risk of nonresponse bias based on Maximal Absolute Bias (MAB), and coefficients of variation between subgroup response rates, alongside the associated costs of different types of fieldwork effort. The results show that increases in response rate help to reduce MAB, while only small but important improvements to sample representativity are gained by varying the type of effort. These findings lend further support to research that has called into question the value of extensive investment in procedures aimed at reaching response rate targets and the need for more tailored fieldwork strategies aimed both at reducing survey costs and minimising the risk of bias.

Reproducibility of species lists, visual cover estimates and frequency methods for recording high mountain vegetation

Question: When multiple observers record the same spatial units of alpine vegetation, how much variation is there in the records and what are the consequences of this variation for monitoring schemes to detect change? Location: One test summit in Switzerland (Alps) and one test summit in Scotland (Cairngorm Mountains). Method: Eight observers used the GLORIA protocols for species composition and visual cover estimates in percent on large summit sections (>100 m2) and species composition and frequency in nested quadrats (1 m2). Results: The multiple records from the same spatial unit for species composition and species cover showed considerable variation in the two countries. Estimates of pseudoturnover of composition and coefficients of variation of cover estimates for vascular plant species in 1m x 1m quadrats showed less variation than in previously published reports whereas our results in larger sections were broadly in line with previous reports. In Scotland, estimates for bryophytes and lichens were more variable than for vascular plants. Conclusions: Statistical power calculations indicated that, unless large numbers of plots were used, changes in cover or frequency were only likely to be detected for abundant species (exceeding 10% cover) or if relative changes were large (50% or more). Lower variation could be reached with the point methods and with larger numbers of small plots. However, as summits often strongly differ from each other, supplementary summits cannot be considered as a way of increasing statistical power without introducing a supplementary component of variance into the analysis and hence the power calculations.

Tire traces: discrimination and classification of pyrolysis-GC/MS profiles

Tire traces can be observed on several crime scenes as vehicles are often used by criminals. The tread abrasion on the road, while braking or skidding, leads to the production of small rubber particles which can be collected for comparison purposes. This research focused on the statistical comparison of Py-GC/MS profiles of tire traces and tire treads. The optimisation of the analytical method was carried out using experimental designs. The aim was to determine the best pyrolysis parameters regarding the repeatability of the results. Thus, the pyrolysis factor effect could also be calculated. The pyrolysis temperature was found to be five time more important than time. Finally, a pyrolysis at 650 °C during 15 s was selected. Ten tires of different manufacturers and models were used for this study. Several samples were collected on each tire, and several replicates were carried out to study the variability within each tire (intravariability). More than eighty compounds were integrated for each analysis and the variability study showed that more than 75% presented a relative standard deviation (RSD) below 5% for the ten tires, thus supporting a low intravariability. The variability between the ten tires (intervariability) presented higher values and the ten most variant compounds had a RSD value above 13%, supporting their high potential of discrimination between the tires tested. Principal Component Analysis (PCA) was able to fully discriminate the ten tires with the help of the first three principal components. The ten tires were finally used to perform braking tests on a racetrack with a vehicle equipped with an anti-lock braking system. The resulting tire traces were adequately collected using sheets of white gelatine. As for tires, the intravariability for the traces was found to be lower than the intervariability. Clustering methods were carried out and the Ward's method based on the squared Euclidean distance was able to correctly group all of the tire traces replicates in the same cluster than the replicates of their corresponding tire. Blind tests on traces were performed and were correctly assigned to their tire source. These results support the hypothesis that the tested tires, of different manufacturers and models, can be discriminated by a statistical comparison of their chemical profiles. The traces were found to be not differentiable from their source but differentiable from all the other tires present in the subset. The results are promising and will be extended on a larger sample set.

Impact of Duration of Primary Education on School Enrollment, Graduation and Drop-outs: A Cross- Country Analysis

Using a panel data for non-OECD countries covering the period 1970-2012, this chapter analyzes the impact of the duration of primary education on school enrollment, drop-out and completion rates. The empirical results show that for children in elementary school one ad- ditional grade of primary education have a negative impact on the enrollment rate, while the e ect on drop-outs is positive. Analogously, it is obtained that an additional grade in primary education reduces the enrollment rate in secondary education. These results are in line with the fertility model approach, that is, in developing and underdeveloped countries parents do not have incentive to send children to school given the high perceived economic value of children.

Repeatability of adaptability and stability parameters of common bean in unpredictable environments

The objective of this work was to estimate the repeatability of adaptability and stability parameters of common bean between years, within each biennium from 2003 to 2012, in Minas Gerais state, Brazil. Grain yield data from trials of value for cultivation and use common bean were analyzed. Grain yield, ecovalence, regression coefficient, and coefficient of determination were estimated considering location and sowing season per year, within each biennium. Subsequently, a analysis of variance these estimates was carried out, and repeatability was estimated in the biennia. Repeatability estimate for grain yield in most of the biennia was relatively high, but for ecovalence and regression coefficient it was null or of small magnitude, which indicates that confidence on identification of common bean lines for recommendation is greater when using means of yield, instead of stability parameters.

Aurinkokeräimien käyttö turpeen kenttäkuivauksessa

Tämä tutkimus tehtiin osana Vapo Oy:n uuden turvetuotantotekniikan kehitystä. Kihniön Aitonevalle on rakennettu uuden turvetuotantotekniikan tutkimusalue, johon kuuluu muun muassa yksi lämmittämätön kuivatuskenttä sekä yksi aurinkolämmöllä lämmitetty kuivatuskenttä aurinkokeräimineen ja putkistoineen. Työn tavoitteena oli selvittää aurinkolämmöllä lämmitetyn kuivatuskentän tuotannon teho verrattuna lämmittämättömään kenttään. Toinen tavoite oli selvittää Aitonevan tutkimusalueella käytössä olevista aurinkokeräimistä turpeen kuivaustarkoitukseen parhaiten soveltuva keräin. Tuotantoa uudella menetelmällä tehtiin vuoden 2005 kesän ajan. Tuotantotehon ero pyrittiin selvittämään seuraamalla yksittäisten turvetuotantoerien eli satokiertojen kuivumista kosteusnäyttein ja toisaalta vertaamalla koko kesän aikana saatua tuotantoa. Aurinkokeräimien vertailu toteutettiin energiamäärä- ja hyötysuhdemittauksin. Lisäksi kuivatuskenttien lämpötiloja mitattiin kentässä tapahtuvan lämmönsiirron selvittämiseksi. Mittausten perusteella havaittiin, ettälämmitetyn ja lämmittämättömän kentän välillä on tutkimuksen aikaisella kenttärakenteella 6-8 % ero satokierron aikana haihdutetussa vesimäärässä. Tätä voidaanpitää odotuksia pienempänä. Kenttien lämpötilamittausten perusteella osoittautui, että kentän pintarakenne tulisi eristää maaperästä, koska kentän alle siirrettyä lämpöä siirtyy häviöinä kylmään pohjamaahan. Käytössä olleista aurinkokeräimistä parhaaksi osoittautui katettu kumimattokeräin niin hyötysuhteen kuin tehokkuudenkin puolesta. Työn aikana todettiin, että tutkimusta keräimien ja varsinkinkenttärakenteen suhteen tulee jatkaa tulevaisuudessa ennen aurinkokeräinkentän laajamittaisen käytön aloittamista.

Modeling growth and yield of loblolly pinestands under intensive management

Abstract:The objective of this work was to develop and validate a prognosis system for volume yield and basal area of intensively managed loblolly pine (Pinus taeda) stands, using stand and diameter class models compatible in basal area estimates. The data used in the study were obtained from plantations located in northern Uruguay. For model validation without data loss, a three-phase validation scheme was applied: first, the equations were fitted without the validation database; then, model validation was carried out; and, finally, the database was regrouped to recalibrate the parameter values. After the validation and final parameterization of the models, a simulation of the first commercial thinning was carried out. The developed prognosis system was precise and accurate in estimating basal area production per hectare or per diameter classes. There was compatibility in basal area estimates between diameter class and whole stand models, with a mean difference of -0.01 m2ha-1. The validation scheme applied is logic and consistent, since information on the accuracy and precision of the models is obtained without the loss of any information in the estimation of the models' parameters.

Microgrids and their operations

Interconnection of loads and small size generation forms a new type of distribution systems, the Microgrid. The microgrids can be operated together with the utility grid or be operated autonomously in an island. Thesesmall grids present a new paradigm of the construction of the low voltage distribution systems. The microgrids in the distribution systems can become small, controllable units, which immediately react to the system's changes. Along with that the microgrids can realize the special properties, such as increasing the reliability, reducing losses, voltage sag correction, uninterruptible supplying. The goals of the thesis are to explain the principles of the microgrid's functioning, to clarify the main ideas and positive features of the microgrids, to find out and prove their advantages and explain why they are so popular nowadays all over the world. The practical aims of the thesis are to construct and build a test setup of a microgrid based on two inverters from SMA Technologie AG in the laboratory and to test all the main modes and parameters of the microgrid's operating. Also the purpose of the thesis is to test the main component of the microgrid - the battery inverter which controls allthe processes and energy flows inside a microgrid and communicates with the main grid. Based on received data the main contribution of the thesis consists of the estimation of the established microgrid from the reliability, economy and simplicity of operating points of view and evaluation ofthe advisability of its use in different conditions. Moreover, the thesis assumes to give the recommendations and advice for the future investigations of the built system.

Systeemihinnan volatiliteetin mallinus Nord Pool -sähkömarkkinoilla

Työssä tarkastellaan, miten Nord Poolin spot-sähkömarkkinoiden systeemihinnan volatiliteetti on kehittynyt kyseisten markkinoiden kehittyessä ja onko volatiliteetin dynamiikkaa mahdollista mallintaa. Systeemihinta toimii referenssihintana sekä itse sähköpörssissä että pörssin ulkopuolella tapahtuvassa johdannaiskaupankäynnissä. Teoriaosassa luodaan katsaus Nord Pool -markkinoiden toimintaan ja systeemihinnan muodostumisen periaatteisiin. Lisäksi tutustutaan sähkön hinta-aikasarjoille tyypillisiin piirteisiin. Volatiliteetin mallinnus tapahtuu autoregressiivistä konditionaalista heteroskedastista (ARCH) mallia sekä sen laajennuksia hyödyntäen. Työn johtopäätöksinä todetaan, että sähkömarkkinoiden volatiliteettia mallinnettaessa tulisi ottaa huomioon hinnan muutosten asymmetrinen vaikutus volatiliteettiin ja volatiliteetin kausittainen vaihtelu. Lisäksi todettiin, etteivätparametrien kertoimet ole vakioita pitkällä aikavälillä tarkasteltaessa volatiliteetin ARCH-mallinnuksessa.

The Munc13 proteins differentially regulate readily releasable pool dynamics and calcium-dependent recovery at a central synapse.

The Munc13 gene family encodes molecules located at the synaptic active zone that regulate the reliability of synapses to encode information over a wide range of frequencies in response to action potentials. In the CNS, proteins of the Munc13 family are critical in regulating neurotransmitter release and synaptic plasticity. Although Munc13-1 is essential for synaptic transmission, it is paradoxical that Munc13-2 and Munc13-3 are functionally dispensable at some synapses, although their loss in other synapses leads to increases in frequency-dependent facilitation. We addressed this issue at the calyx of Held synapse, a giant glutamatergic synapse that we found to express all these Munc13 isoforms. We studied their roles in the regulation of synaptic transmission and their impact on the reliability of information transfer. Through detailed electrophysiological analyses of Munc13-2, Munc13-3, and Munc13-2-3 knock-out and wild-type mice, we report that the combined loss of Munc13-2 and Munc13-3 led to an increase in the rate of calcium-dependent recovery and a change in kinetics of release of the readily releasable pool. Furthermore, viral-mediated overexpression of a dominant-negative form of Munc13-1 at the calyx demonstrated that these effects are Munc13-1 dependent. Quantitative immunohistochemistry using Munc13-fluorescent protein knock-in mice revealed that Munc13-1 is the most highly expressed Munc13 isoform at the calyx and the only one highly colocalized with Bassoon at the active zone. Based on these data, we conclude that Munc13-2 and Munc13-3 isoforms limit the ability of Munc13-1 to regulate calcium-dependent replenishment of readily releasable pool and slow pool to fast pool conversion in central synapses.

Use of the dried blood spot sampling process coupled with fast gas chromatography and negative-ion chemical ionization tandem mass spectrometry: application to fluoxetine, norfluoxetine, reboxetine, and paroxetine analysis.

The objective of this work was to combine the advantages of the dried blood spot (DBS) sampling process with the highly sensitive and selective negative-ion chemical ionization tandem mass spectrometry (NICI-MS-MS) to analyze for recent antidepressants including fluoxetine, norfluoxetine, reboxetine, and paroxetine from micro whole blood samples (i.e., 10 microL). Before analysis, DBS samples were punched out, and antidepressants were simultaneously extracted and derivatized in a single step by use of pentafluoropropionic acid anhydride and 0.02% triethylamine in butyl chloride for 30 min at 60 degrees C under ultrasonication. Derivatives were then separated on a gas chromatograph coupled with a triple-quadrupole mass spectrometer operating in negative selected reaction monitoring mode for a total run time of 5 min. To establish the validity of the method, trueness, precision, and selectivity were determined on the basis of the guidelines of the "Société Française des Sciences et des Techniques Pharmaceutiques" (SFSTP). The assay was found to be linear in the concentration ranges 1 to 500 ng mL(-1) for fluoxetine and norfluoxetine and 20 to 500 ng mL(-1) for reboxetine and paroxetine. Despite the small sampling volume, the limit of detection was estimated at 20 pg mL(-1) for all the analytes. The stability of DBS was also evaluated at -20 degrees C, 4 degrees C, 25 degrees C, and 40 degrees C for up to 30 days. Furthermore, the method was successfully applied to a pharmacokinetic investigation performed on a healthy volunteer after oral administration of a single 40-mg dose of fluoxetine. Thus, this validated DBS method combines an extractive-derivative single step with a fast and sensitive GC-NICI-MS-MS technique. Using microliter blood samples, this procedure offers a patient-friendly tool in many biomedical fields such as checking treatment adherence, therapeutic drug monitoring, toxicological analyses, or pharmacokinetic studies.