996 resultados para ex parte application for freezing order


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Scopo della presente trattazione è quello di andare ad osservare in che modo il legislatore della riforma abbia cercato di offrire una disciplina ad un fenomeno sempre più in espansione nell’economia italiana: i gruppi di impresa. In particolare, l’elaborato è composto da 3 nuclei. Il primo analizza la disciplina, introdotta nel 2003, relativa all’attività di direzione e coordinamento (art. 2497 c.c. e ss) rintracciandone le regole generali e il rapporto con le norme del codice civile. Una seconda parte approfondisce gli elementi costitutivi dell'attivita' di direzione e coordinamento, i presupposti affinche' si possa configurare una responsabilita' da parte della societa' capogruppo e i soggetti conivolti all'interno di un gruppo. La terza parte e' invece dedicata allo studio delle problematiche legate all’azione risarcitoria introdotta con la disposizione di cui all’art. 2497 c.c., soprattutto confrontando la posizione dei soci di minoranza con quella dei creditori sociali. In particolare, vengono descritte le modalità con le quali i soci e i creditori sociali possono esercitare l’azione a tutela dei propri interessi e dunque tentare di trovare pieno ristoro ai danni sofferti; danni che in qualche modo risultano legati alle scelte operate dal gruppo di comando e, più tecnicamente, dalla società che esercita l’attività di direzione e coordinamento, la c.d. capogruppo.

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Recientemente, el paradigma de la computación en la nube ha recibido mucho interés por parte tanto de la industria como del mundo académico. Las infraestructuras cloud públicas están posibilitando nuevos modelos de negocio y ayudando a reducir costes. Sin embargo, una compañía podría desear ubicar sus datos y servicios en sus propias instalaciones, o tener que atenerse a leyes de protección de datos. Estas circunstancias hacen a las infraestructuras cloud privadas ciertamente deseables, ya sea para complementar a las públicas o para sustituirlas por completo. Por desgracia, las carencias en materia de estándares han impedido que las soluciones para la gestión de infraestructuras privadas se hayan desarrollado adecuadamente. Además, la multitud de opciones disponibles ha creado en los clientes el miedo a depender de una tecnología concreta (technology lock-in). Una de las causas de este problema es la falta de alineación entre la investigación académica y los productos comerciales, ya que aquella está centrada en el estudio de escenarios idealizados sin correspondencia con el mundo real, mientras que éstos consisten en soluciones desarrolladas sin tener en cuenta cómo van a encajar con los estándares más comunes o sin preocuparse de hacer públicos sus resultados. Con objeto de resolver este problema, propongo un sistema de gestión modular para infraestructuras cloud privadas enfocado en tratar con las aplicaciones en lugar de centrarse únicamente en los recursos hardware. Este sistema de gestión sigue el paradigma de la computación autónoma y está diseñado en torno a un modelo de información sencillo, desarrollado para ser compatible con los estándares más comunes. Este modelo divide el entorno en dos vistas, que sirven para separar aquello que debe preocupar a cada actor involucrado del resto de información, pero al mismo tiempo permitiendo relacionar el entorno físico con las máquinas virtuales que se despliegan encima de él. En dicho modelo, las aplicaciones cloud están divididas en tres tipos genéricos (Servicios, Trabajos de Big Data y Reservas de Instancias), para que así el sistema de gestión pueda sacar partido de las características propias de cada tipo. El modelo de información está complementado por un conjunto de acciones de gestión atómicas, reversibles e independientes, que determinan las operaciones que se pueden llevar a cabo sobre el entorno y que es usado para hacer posible la escalabilidad en el entorno. También describo un motor de gestión encargado de, a partir del estado del entorno y usando el ya mencionado conjunto de acciones, la colocación de recursos. Está dividido en dos niveles: la capa de Gestores de Aplicación, encargada de tratar sólo con las aplicaciones; y la capa del Gestor de Infraestructura, responsable de los recursos físicos. Dicho motor de gestión obedece un ciclo de vida con dos fases, para así modelar mejor el comportamiento de una infraestructura real. El problema de la colocación de recursos es atacado durante una de las fases (la de consolidación) por un resolutor de programación entera, y durante la otra (la online) por un heurístico hecho ex-profeso. Varias pruebas han demostrado que este acercamiento combinado es superior a otras estrategias. Para terminar, el sistema de gestión está acoplado a arquitecturas de monitorización y de actuadores. Aquella estando encargada de recolectar información del entorno, y ésta siendo modular en su diseño y capaz de conectarse con varias tecnologías y ofrecer varios modos de acceso. ABSTRACT The cloud computing paradigm has raised in popularity within the industry and the academia. Public cloud infrastructures are enabling new business models and helping to reduce costs. However, the desire to host company’s data and services on premises, and the need to abide to data protection laws, make private cloud infrastructures desirable, either to complement or even fully substitute public oferings. Unfortunately, a lack of standardization has precluded private infrastructure management solutions to be developed to a certain level, and a myriad of diferent options have induced the fear of lock-in in customers. One of the causes of this problem is the misalignment between academic research and industry ofering, with the former focusing in studying idealized scenarios dissimilar from real-world situations, and the latter developing solutions without taking care about how they f t with common standards, or even not disseminating their results. With the aim to solve this problem I propose a modular management system for private cloud infrastructures that is focused on the applications instead of just the hardware resources. This management system follows the autonomic system paradigm, and is designed around a simple information model developed to be compatible with common standards. This model splits the environment in two views that serve to separate the concerns of the stakeholders while at the same time enabling the traceability between the physical environment and the virtual machines deployed onto it. In it, cloud applications are classifed in three broad types (Services, Big Data Jobs and Instance Reservations), in order for the management system to take advantage of each type’s features. The information model is paired with a set of atomic, reversible and independent management actions which determine the operations that can be performed over the environment and is used to realize the cloud environment’s scalability. From the environment’s state and using the aforementioned set of actions, I also describe a management engine tasked with the resource placement. It is divided in two tiers: the Application Managers layer, concerned just with applications; and the Infrastructure Manager layer, responsible of the actual physical resources. This management engine follows a lifecycle with two phases, to better model the behavior of a real infrastructure. The placement problem is tackled during one phase (consolidation) by using an integer programming solver, and during the other (online) with a custom heuristic. Tests have demonstrated that this combined approach is superior to other strategies. Finally, the management system is paired with monitoring and actuators architectures. The former able to collect the necessary information from the environment, and the later modular in design and capable of interfacing with several technologies and ofering several access interfaces.

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This paper presents a comparison between proportional integral control approaches for variable speed wind turbines. Integer and fractional-order controllers are designed using linearized wind turbine model whilst fuzzy controller also takes into account system nonlinearities. These controllers operate in the full load region and the main objective is to extract maximum power from the wind turbine while ensuring the performance and reliability required to be integrated into an electric grid. The main contribution focuses on the use of fractional-order proportional integral (FOPI) controller which benefits from the introduction of one more tuning parameter, the integral fractional-order, taking advantage over integer order proportional integral (PI) controller. A comparison between proposed control approaches for the variable speed wind turbines is presented using a wind turbine benchmark model in the Matlab/Simulink environment. Results show that FOPI has improved system performance when compared with classical PI and fuzzy PI controller outperforms the integer and fractional-order control due to its capability to deal with system nonlinearities and uncertainties. © 2014 IEEE.

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This paper presents a comparison between proportional integral control approaches for variable speed wind turbines. Integer and fractional-order controllers are designed using linearized wind turbine model whilst fuzzy controller also takes into account system nonlinearities. These controllers operate in the full load region and the main objective is to extract maximum power from the wind turbine while ensuring the performance and reliability required to be integrated into an electric grid. The main contribution focuses on the use of fractional-order proportional integral (FOPI) controller which benefits from the introduction of one more tuning parameter, the integral fractional-order, taking advantage over integer order proportional integral (PI) controller. A comparison between proposed control approaches for the variable speed wind turbines is presented using a wind turbine benchmark model in the Matlab/Simulink environment. Results show that FOPI has improved system performance when compared with classical PI and fuzzy PI controller outperforms the integer and fractional-order control due to its capability to deal with system nonlinearities and uncertainties. © 2014 IEEE.

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Fractional calculus (FC) is currently being applied in many areas of science and technology. In fact, this mathematical concept helps the researches to have a deeper insight about several phenomena that integer order models overlook. Genetic algorithms (GA) are an important tool to solve optimization problems that occur in engineering. This methodology applies the concepts that describe biological evolution to obtain optimal solution in many different applications. In this line of thought, in this work we use the FC and the GA concepts to implement the electrical fractional order potential. The performance of the GA scheme, and the convergence of the resulting approximation, are analyzed. The results are analyzed for different number of charges and several fractional orders.

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Fractional calculus (FC) is widely used in most areas of science and engineering, being recognized its ability to yield a superior modeling and control in many dynamical systems. In this perspective, this article illustrates two applications of FC in the area of control systems. Firstly, is presented a methodology of tuning PID controllers that gives closed-loop systems robust to gain variations. After, a fractional-order PID controller is proposed for the control of an hexapod robot with three dof legs. In both cases, it is demonstrated the system's superior performance by using the FC concepts.

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A new very high-order finite volume method to solve problems with harmonic and biharmonic operators for one- dimensional geometries is proposed. The main ingredient is polynomial reconstruction based on local interpolations of mean values providing accurate approximations of the solution up to the sixth-order accuracy. First developed with the harmonic operator, an extension for the biharmonic operator is obtained, which allows designing a very high-order finite volume scheme where the solution is obtained by solving a matrix-free problem. An application in elasticity coupling the two operators is presented. We consider a beam subject to a combination of tensile and bending loads, where the main goal is the stress critical point determination for an intramedullary nail.

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In this article, we explore the contractual design of toll road concession contracts. We highlight the fact that contracting parties try to sign not only complete rigid contracts in order to avoid renegotiations but also flexible contracts in order to adapt contractual framework to contingencies and to create incentives for cooperative behavior. This gives rise to multiple toll adjustment provisions and to a tradeoff between rigid and flexible contracts. Such a tradeoff is formalized using an incomplete contract framework - including ex post maladaptation and renegotiation costs - and propositions are tested using an original database of 71 concession contracts. Our results suggest an important role for economic efficiency concerns, as well as politics, in designing such public-private contracts. Codes JEL : D23, H11, H54, L14, L9.

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THESIS ABSTRACT : Low-temperature thermochronology relies on application of radioisotopic systems whose closure temperatures are below temperatures at which the dated phases are formed. In that sense, the results are interpreted as "cooling ages" in contrast to "formation ages". Owing to the low closure-temperatures, it is possible to reconstruct exhumation and cooling paths of rocks during their residence at shallow levels of the crust, i.e. within first ~10 km of depth. Processes occurring at these shallow depths such as final exhumation, faulting and relief formation are fundamental for evolution of the mountain belts. This thesis aims at reconstructing the tectono-thermal history of the Aar massif in the Central Swiss Alps by means of zircon (U-Th)/He, apatite (U-Th)/He and apatite fission track thermochronology. The strategy involved acquisition of a large number of samples from a wide range of elevations in the deeply incised Lötschen valley and a nearby NEAT tunnel. This unique location allowed to precisely constrain timing, amount and mechanisms of exhumation of the main orographic feature of the Central Alps, evaluate the role of topography on the thermochronological record and test the impact of hydrothermal activity. Samples were collected from altitudes ranging between 650 and 3930 m and were grouped into five vertical profiles on the surface and one horizontal in the tunnel. Where possible, all three radiometric systems were applied to each sample. Zircon (U-Th)/He ages range from 5.1 to 9.4 Ma and are generally positively correlated with altitude. Age-elevation plots reveal a distinct break in slope, which translates into exhumation rate increasing from ~0.4 to ~3 km/Ma at 6 Ma. This acceleration is independently confirmed by increased cooling rates on the order of 100°C/Ma constrained on the basis of age differences between the zircon (U-Th)/He and the remaining systems. Apatite fission track data also plot on a steep age-elevation curve indicating rapid exhumation until the end of the Miocene. The 6 Ma event is interpreted as reflecting tectonically driven uplift of the Aar massif. The late Miocene timing implies that the increase of precipitation in the Pliocene did not trigger rapid exhumation in the Aar massif. The Messinian salinity crisis in the Mediterranean could not directly intensify erosion of the Aar but associated erosional output from the entire Alps may have tapered the orogenic wedge and caused reactivation of thrusting in the Aar massif. The high exhumation rates in the Messinian were followed by a decrease to ~1.3 km/Ma as evidenced by ~8 km of exhumation during last 6 Ma. The slowing of exhumation is also apparent from apatite (U-Th)1He age-elevation data in the northern part of the Lötschen valley where they plot on a ~0.5km/Ma line and range from 2.4 to 6.4 Ma However, from the apatite (U-Th)/He and fission track data from the NEAT tunnel, there is an indication of a perturbation of the record. The apatite ages are youngest under the axis of the valley, in contrast to an expected pattern where they would be youngest in the deepest sections of the tunnel due to heat advection into ridges. The valley however, developed in relatively soft schists while the ridges are built of solid granitoids. In line with hydrological observations from the tunnel, we suggest that the relatively permeable rocks under the valley floor, served as conduits of geothermal fluids that caused reheating leading to partial Helium loss and fission track annealing in apatites. In consequence, apatite ages from the lowermost samples are too young and the calculated exhumation rates may underestimate true values. This study demonstrated that high-density sampling is indispensable to provide meaningful thermochronological data in the Alpine setting. The multi-system approach allows verifying plausibility of the data and highlighting sources of perturbation. RÉSUMÉ DE THÈSE : La thermochronologie de basse température dépend de l'utilisation de systèmes radiométriques dont la température de fermeture est nettement inférieure à la température de cristallisation du minéral. Les résultats obtenus sont par conséquent interprétés comme des âges de refroidissement qui diffèrent des âges de formation obtenus par le biais d'autres systèmes de datation. Grâce aux températures de refroidissement basses, il est aisé de reconstruire les chemins de refroidissement et d'exhumation des roches lors de leur résidence dans la croute superficielle (jusqu'à 10 km). Les processus qui entrent en jeu à ces faibles profondeurs tels que l'exhumation finale, la fracturation et le faillage ainsi que la formation du relief sont fondamentaux dans l'évolution des chaînes de montagne. Ces dernières années, il est devenu clair que l'enregistrement thermochronologique dans les orogènes peut être influencé par le relief et réinitialisé par l'advection de la chaleur liée à la circulation de fluides géothermaux après le refroidissement initial. L'objectif de cette thèse est de reconstruire l'histoire tectono-thermique du massif de l'Aar dans les Alpes suisses Centrales à l'aide de trois thermochronomètres; (U-Th)/He sur zircon, (U-Th)/He sur apatite et les traces de fission sur apatite. Afin d'atteindre cet objectif, nous avons récolté un grand nombre d'échantillons provenant de différentes altitudes dans la vallée fortement incisée de Lötschental ainsi que du tunnel de NEAT. Cette stratégie d'échantillonnage nous a permis de contraindre de manière précise la chronologie, les quantités et les mécanismes d'exhumation de cette zone des Alpes Centrales, d'évaluer le rôle de la topographie sur l'enregistrement thermochronologique et de tester l'impact de l'hydrothermalisme sur les géochronomètres. Les échantillons ont été prélevés à des altitudes comprises entre 650 et 3930m selon 5 profils verticaux en surface et un dans le tunnel. Quand cela à été possible, les trois systèmes radiométriques ont été appliqués aux échantillons. Les âges (U-Th)\He obtenus sur zircons sont compris entre 5.l et 9.4 Ma et sont corrélés de manière positive avec l'altitude. Les graphiques représentant l'âge et l'élévation montrent une nette rupture de la pente qui traduisent un accroissement de la vitesse d'exhumation de 0.4 à 3 km\Ma il y a 6 Ma. Cette accélération de l'exhumation est confirmée par les vitesses de refroidissement de l'ordre de 100°C\Ma obtenus à partir des différents âges sur zircons et à partir des autres systèmes géochronologiques. Les données obtenues par traces de fission sur apatite nous indiquent également une exhumation rapide jusqu'à la fin du Miocène. Nous interprétons cet évènement à 6 Ma comme étant lié à l'uplift tectonique du massif de l'Aar. Le fait que cet évènement soit tardi-miocène implique qu'une augmentation des précipitations au Pliocène n'a pas engendré cette exhumation rapide du massif de l'Aar. La crise Messinienne de la mer méditerranée n'a pas pu avoir une incidence directe sur l'érosion du massif de l'Aar mais l'érosion associée à ce phénomène à pu réduire le coin orogénique alpin et causer la réactivation des chevauchements du massif de l'Aar. L'exhumation rapide Miocène a été suivie pas une diminution des taux d'exhumation lors des derniers 6 Ma (jusqu'à 1.3 km\Ma). Cependant, les âges (U-Th)\He sur apatite ainsi que les traces de fission sur apatite des échantillons du tunnel enregistrent une perturbation de l'enregistrement décrit ci-dessus. Les âges obtenus sur les apatites sont sensiblement plus jeunes sous l'axe de la vallée en comparaison du profil d'âges attendus. En effet, on attendrait des âges plus jeunes sous les parties les plus profondes du tunnel à cause de l'advection de la chaleur dans les flancs de la vallée. La vallée est creusée dans des schistes alors que les flancs de celle-ci sont constitués de granitoïdes plus durs. En accord avec les observations hydrologiques du tunnel, nous suggérons que la perméabilité élevée des roches sous l'axe de la vallée à permi l'infiltration de fluides géothermaux qui a généré un réchauffement des roches. Ce réchauffement aurait donc induit une perte d'Hélium et un recuit des traces de fission dans les apatites. Ceci résulterait en un rajeunissement des âges apatite et en une sous-estimation des vitesses d'exhumation sous l'axe de la vallée. Cette étude à servi à démontrer la nécessité d'un échantillonnage fin et précis afin d'apporter des données thermochronologiques de qualité dans le contexte alpin. Cette approche multi-système nous a permi de contrôler la pertinence des données acquises ainsi que d'identifier les sources possibles d'erreurs lors d'études thermochronologiques. RÉSUMÉ LARGE PUBLIC Lors d'une orogenèse, les roches subissent un cycle comprenant une subduction, de la déformation, du métamorphisme et, finalement, un retour à la surface (ou exhumation). L'exhumation résulte de la déformation au sein de la zone de collision, menant à un raccourcissement et un apaissessement de l'édifice rocheux, qui se traduit par une remontée des roches, création d'une topographie et érosion. Puisque l'érosion agit comme un racloir sur la partie supérieure de l'édifice, des tentatives de corrélation entre les épisodes d'exhumation rapide et les périodes d'érosion intensive, dues aux changements climatiques, ont été effectuées. La connaissance de la chronologie et du lieu précis est d'une importance capitale pour une quelconque reconstruction de l'évolution d'une chaîne de montagne. Ces critères sont donnés par un retraçage des changements de la température de la roche en fonction du temps, nous donnant le taux de refroidissement. L'instant auquel les roches ont refroidit, passant une certaine température, est contraint par l'application de techniques de datation par radiométrie. Ces méthodes reposent sur la désintégration des isotopes radiogéniques, tels que l'uranium et le potassium, tous deux abondants dans les roches de la croûte terrestre. Les produits de cette désintégration ne sont pas retenus dans les minéraux hôtes jusqu'au moment du refroidissement de la roche sous une température appelée 'de fermeture' , spécifique à chaque système de datation. Par exemple, la désintégration radioactive des atomes d'uranium et de thorium produit des atomes d'hélium qui s'échappent d'un cristal de zircon à des températures supérieures à 200°C. En mesurant la teneur en uranium-parent, l'hélium accumulé et en connaissant le taux de désintégration, il est possible de calculer à quel moment la roche échantillonnée est passée sous la température de 200°C. Si le gradient géothermal est connu, les températures de fermeture peuvent être converties en profondeurs actuelles (p. ex. 200°C ≈ 7km), et le taux de refroidissement en taux d'exhumation. De plus, en datant par système radiométrique des échantillons espacés verticalement, il est possible de contraindre directement le taux d'exhumation de la section échantillonnée en observant les différences d'âges entre des échantillons voisins. Dans les Alpes suisses, le massif de l'Aar forme une structure orographique majeure. Avec des altitudes supérieures à 4000m et un relief spectaculaire de plus de 2000m, le massif domine la partie centrale de la chaîne de montagne. Les roches aujourd'hui exposées à la surface ont été enfouies à plus de 10 km de profond il y a 20 Ma, mais la topographie actuelle du massif de l'Aar semble surtout s'être développée par un soulèvement actif depuis quelques millions d'années, c'est-à-dire depuis le Néogène supérieur. Cette période comprend un changement climatique soudain ayant touché l'Europe il y a environ 5 Ma et qui a occasionné de fortes précipitations, entraînant certainement une augmentation de l'érosion et accélérant l'exhumation des Alpes. Dans cette étude, nous avons employé le système de datation (U-TH)/He sur zircon, dont la température de fermeture de 200°C est suffisamment basse pour caractériser l'exhumation du Néogène sup. /Pliocène. Les échantillons proviennent du Lötschental et du tunnel ferroviaire le plus profond du monde (NEAT) situé dans la partie ouest du massif de l'Aar. Considérés dans l'ensemble, ces échantillons se répartissent sur un dénivelé de 3000m et des âges de 5.1 à 9.4 Ma. Les échantillons d'altitude supérieure (et donc plus vieux) documentent un taux d'exhumation de 0.4 km/Ma jusqu'à il y a 6 Ma, alors que les échantillons situés les plus bas ont des âges similaires allant de 6 à 5.4 Ma, donnant un taux jusqu'à 3km /Ma. Ces données montrent une accélération dramatique de l'exhumation du massif de l'Aar il y a 6 Ma. L'exhumation miocène sup. du massif prédate donc le changement climatique Pliocène. Cependant, lors de la crise de salinité d'il y a 6-5.3 Ma (Messinien), le niveau de la mer Méditerranée est descendu de 3km. Un tel abaissement de la surface d'érosion peut avoir accéléré l'exhumation des Alpes, mais le bassin sud alpin était trop loin du massif de l'Aar pour influencer son érosion. Nous arrivons à la conclusion que la datation (U-Th)/He permet de contraindre précisément la chronologie et l'exhumation du massif de l'Aar. Concernant la dualité tectonique-érosion, nous suggérons que, dans le cas du massif de l'Aar, la tectonique prédomine.

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This is a critical review of the medical, ethical, judicial and financial aspects of the so called "social freezing", the cryopreservation of a woman's oocytes for non-medical purposes. The possibility of storing the eggs of fertile women in order to prevent age-related fertility decline is being widely promoted by fertility centres and the lay press throughout the world. Research data has shown that social freezing should ideally be performed on women around 25 years of age in order to increase their chances of a future pregnancy. In reality, it is mostly performed after the age of 35. Unfortunately, social freezing is in general not a solution for the underlying societal problems to fit in with professionally active women and having children. It only delays the existing problems. Furthermore, it creates a lot of potential new problems. A great deal more should be undertaken to offer real solutions to the underlying societal problems which are in part: pre-school education, care in the event of childhood illness, and the many weeks of school holidays, acceptance of professionally active women having children, and more job offers with a workload <100%.). Furthermore, society should be informed about the decreasing chances of pregnancy with increasing maternal (and paternal) age as well as the increasing risks of miscarriage and obstetric/neonatal complications. Detailed information for woman considering social freezing is crucial. Every doctor, proposing social freezing to his patients, should be up to date with all these details. Follow-up studies on the outcome of these children are needed.

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Appoints the Des Moines resident-in-charge for the U.S. Drug Enforcement Adminstration as a nonvoting ex-officio member of the Iowa Law Enforcement Academy Council.

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In this paper, we examine the design of permit trading programs when the objective is to minimize the cost of achieving an ex ante pollution target, that is, one that is defined in expectation rather than an ex post deterministic value. We consider two potential sources of uncertainty, the presence of either of which can make our model appropriate: incomplete information on abatement costs and uncertain delivery coefficients. In such a setting, we find three distinct features that depart from the well-established results on permit trading: (1) the regulator’s information on firms’ abatement costs can matter; (2) the optimal permit cap is not necessarily equal to the ex ante pollution target; and (3) the optimal trading ratio is not necessarily equal to the delivery coefficient even when it is known with certainty. Intuitively, since the regulator is only required to meet a pollution target on average, she can set the trading ratio and total permit cap such that there will be more pollution when abatement costs are high and less pollution when abatement costs are low. Information on firms’ abatement costs is important in order for the regulator to induce the optimal alignment between pollution level and abatement costs.

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Report on a review of selected general and application controls over the Iowa State University of Science and Technology (Iowa State University) Purchase Order/Requisition System for the period of March 20 through April 28, 2009

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Cyclosporine A is a poorly water-soluble, immunosuppressive drug used to treat a variety of ocular diseases. Its limited solubility makes challenging the development of a cyclosporine A-based eye drop for ocular topical application. Based on the prodrug strategy, the practically insoluble cyclosporine A was converted into a freely soluble prodrug. Such a water-soluble prodrug made it possible to develop water-based concentrated eye drops. The prodrug formulations were tested for their ex vivo permeation and in vivo distribution at three concentrations (equivalent to 0.05%, 0.50% and 2.00% w/v cyclosporine A). The ex vivo permeation experiments were performed on corneal and conjunctival epithelia. The in vivo distribution evaluated the total cyclosporine A present in the ocular structures as well as in serum, spleen and cervical lymphatic ganglions. Each prodrug formulation was compared to conventionally used cyclosporine A eye drops at an equivalent concentration. The experimental results showed that the tested eye drops behaved differently. The prodrug formulation was characterized by the following: i) preferential conjunctival penetration, ii) an interesting capacity to create large tissue deposits and iii) a lower risk of systemic complications and immunosuppression. The prodrug aqueous eye drop was demonstrated to be a patient-friendly option for the treatment of ocular diseases requiring high ocular levels of cyclosporine A, pushing the boundaries of the current therapeutic arsenal.

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The Wigner higher order moment spectra (WHOS)are defined as extensions of the Wigner-Ville distribution (WD)to higher order moment spectra domains. A general class oftime-frequency higher order moment spectra is also defined interms of arbitrary higher order moments of the signal as generalizations of the Cohen’s general class of time-frequency representations. The properties of the general class of time-frequency higher order moment spectra can be related to theproperties of WHOS which are, in fact, extensions of the properties of the WD. Discrete time and frequency Wigner higherorder moment spectra (DTF-WHOS) distributions are introduced for signal processing applications and are shown to beimplemented with two FFT-based algorithms. One applicationis presented where the Wigner bispectrum (WB), which is aWHOS in the third-order moment domain, is utilized for thedetection of transient signals embedded in noise. The WB iscompared with the WD in terms of simulation examples andanalysis of real sonar data. It is shown that better detectionschemes can be derived, in low signal-to-noise ratio, when theWB is applied.