WO2006108420A1

WO2006108420A1 - Inflatable medical device comprising a permeable membrane

Info

Publication number: WO2006108420A1
Application number: PCT/DK2006/000205
Authority: WO
Inventors: Erik Andersen
Original assignee: Millimed A/S
Priority date: 2005-04-12
Filing date: 2006-04-12
Publication date: 2006-10-19

Abstract

An inflatable medical device for expansion in a body duct, e.g. for use ir invasive procedures. The medical device defines a lumen and a membrane (4,5) which essentially encloses the lumen. The membrane is adapted to expand by i pplicatio® of a pressure in the lumen, and the membrane has a structure that allows gas [14) and/or liquid (13) to diffuse from the lumen to a surrounding tissue, and which prev ants liquid from diffusing from the surrounding tissue into the lumen. A gas and/or liquid! comprisi ig nitric oxide can be used to prevent inflammation, to prevent arterial spasms, eic. Furthermore, the medical device can be used for e.g. thrombectomy.

Description

INFLATABLE MEDICAL DEVICE COMPRISING A PERMEABLE MEMBRANE

Technical field

The present invention relates to an inflatable medical device for the treatment of cell disorder, e.g. for use in invasive procedures and its preparation. The medical device comprises a permeable membrane adapted to expand when the medical device is pressurized.

Background of the invention

Angioplasty balloons are widely used in various intravascular procedures and medical treatments. For example, balloons are employed to expand stents for implantation in the lumen of a body duct for the treatment of blood vessels exhibiting stenosis. It is generally desired that medical devices for insertion in the vascular system of a living being meet certain physical requirements. For example, the surface of medical devices should be hydrophilic and have a low surface friction in order to facilitate introduction. Furthermore, the medical devices must be able to conform to an often torturous passage to the treatment site while being sufficiently rigid to enable secure insertion.

International patent application WO 2004/006976 suggests a single layer of lipophilic bioactive material posited or applied to a balloon base material for direct application to a vessel wall after the previous introduction of a stent. According to the disclosure of the document, the balloon could be used for an angioplasty procedure without the use of a stent. The layer of bioactive material can be posited on the balloon by dipping, soaking or spraying.

In the prior art, various medical devices, including balloons, stents and catheters, as well as methods for their manufacture have been proposed. US patent No. 6,030,371 discloses a method for non-extrusion manufacturing of catheters. A polymer material in a particulate preform is applied in a layer over an outer surface of a core member. By applying the layer in a particulate preform, a composition of the polymer material can be varied continuously as it is being applied to provide a variable hardness over the length of the catheter. A fibrous reinforcement can be used having a constant or variable pitch, and a constant or variable number of fibers and fiber types may be employed.

Various nitric oxide donor components, pharmaceutical compositions containing such nitric oxide donor components and polymeric compositions capable of releasing nitric oxide have also been proposed in the prior art. For example, US patent No. 6,737,447 Bl discloses a medical device comprising at least one nanofiber of a linear poly(etihylenimine) diazeniumdiolate forming a coating layer on the device. US 6,737,447 mentions the possibility of depositing the polymer by an electrospinning process.

US patent IMo. 4,323,525 discloses a process for electrostatically spinning a fiber forming material. The process of electrostatic spinning involves the introduction of a liquid into an electric field whereby the liquid is caused to produce fibers. The spun fiber is collected on a removable sheath on a rotating mandrel. The sheath is electroconductive. The tubular spun fiber product is separated from the sheath.

Summary of the invention

It is an object of embodiments of the present invention to provide an inflatable medical device which allows for improved delivery of pharmaceutically active substances in the lumen of a body duct.

In a first aspect, the invention provides an inflatable medical device for expansion in a body duct, the medical device defining a lumen and a membrane which essentially encloses the lumen, the membrane being adapted to expand by application of a pressure in the lumen, the membrane having a structure that allows gas and/or liquid to diffuse from the lumen to a surrounding tissue, and which prevents liquid from diffusing from the surrounding tissue into the lumen.

Thanks to the permeable membrane, pharmaceutically active substance on gaseous or liquid form may be delivered to a body tissue surrounding the medical device by filling the lumen of the medical device with gas or liquid containing the pharmaceutically active substance, the gas or liquid being possibly pressurized. Thus, large amounts of pharmaceutically active substance may be delivered in a short time, whereas prior art coated devices, such as coated stents usually have a more limited capacity for pharmaceutically active substances and a more limited capability of releasing these substances swiftly. Moreover, as body fluid cannot penetrate the medical device of the present invention, there is no risk of contamination of the lumen of the medical device by body fluid, even if the pressure in the balloon is decreased, e.g. for deflation of the medical device.

The body duct may be a natural body duct present in a patient's body or it may be a duct obtained by surgery. The inflatable medical device may be compliant or non-compliant, a compliant medical device being inflatable in a non-predefined form, whereas a non-compliant medical device will expand in a predefined form. The medical device may be used in e.g. angioplasty procedures, as a stent delivery system, for the treatment of restenosis and for the treatment of cell disorder in a body duct e.g. by the use of nitric oxide. Furthermore, a compliant medical device may be used for thrombectomy where the inflated device may be used to remove material from a duct, e.g. the medical device may be used to remove thrombus or a blood clot from a vessel.

It will be appreciated that a body of the medical device may be essentially constituted by the membrane. In one embodiment of the present invention, the body of the medical device comprises a framework formed by at least one essentially inelastic filament wound around a circumference of the medical device, whereby interstices are provided between portions of the filament, and wherein the permeable membrane comprises an elastic material filling the interstices. The elastic material may be a filament formed from e.g. nanofibers. During manufacture of the medical device, an inner layer of elastic material may be formed on a mandrel, and subsequently the essentially inelastic filament may be wound around the inner layer of material, followed by application of the elastic material filling the interstices between the filament portions. The inelastic filament may be made from inelastic nylon, polyester,

Kevlar^®, or carbonfiber. For example, the medical device may constitute a balloon portion of a dilation catheter, or with the inelastic filaments of the medical device being arranged as disclosed in US patent No. 4,706,670, which is hereby incorporated by reference.

The inner layer of elastic material, which may be formed on a mandrel, may be essentially made from permeable urethane, such as Carbothane^® commercially available from Noveon Inc. The required permeability of the elastic material in the membrane may be achieved by forming nanofibers of the urethane. The urethane may be chosen hydrophobic or hygroscopic according to needed permeability (needed barrier level). The elastic material filling the interstices may be made from the same material, and may also be made from nanofibers. Typically, the diameter of the nanofibers is in the range of 2 to 4000 nanometers, preferably 2-3000 nanometers, and accordingly a large number of nanofibers may be present on the membrane.

The applied nanofibers may be electrospun. It has been found that electrospinning of nanofibers in many instances may be more easily or accurately controlled than methods relying solely on spraying of polymers toward a core. This may confer the further advantage that medical devices may be made with smaller dimensions, such as smaller dimensions that hitherto. The present invention allows for the manufacture of medical devices with relative low diameters which, in comparison to devices with larger diameters, facilitate introduction into a living being and reduce side-effects which may occur as a consequence of the introduction of the medical device. The spinning of nanofibers allows for the manufacture of integrated composite devices, in which two or more materials are interlocked on a molecular scale in small dimensions while maintaining a sufficient mechanical stability. Cross-sectional dimensions as small as the dimension of approximately 2-5 molecules of the spun material may be achieved. The size of the molecules evidently depends on the source material used, the size of a polyurethane molecule being usually in the range of less than 3000 nanometers. Furthermore, electrospun nanofibers are useful as reservoirs for pharmaceutically active substances to be released at a treatment site.

Electrospinning comprises a process of formation of fibers from a fluid exploiting the interactions between surface tension and the electrostatic forces exerted in the fluid surface by an applied electrostatic field. When an electrostatic field is applied to e.g. a droplet of conducting fluid, the fluid surface will experience forces both due to the surface tension as well as due to the applied electrostatic field. At comparably low electrostatic fields the surface tension of the fluid will dominate and the droplet will essentially remain spherical. When the electrostatic field is increased the droplet will become increasingly deformed by electrostatic forces until the surface of the droplet becomes unstable and a tiny stream of liquid is ejected from the surface. The material in this stream eventually solidifies, thus forming a fiber.

Furthermore, it should be understood that the term electrospinning may comprise a process wherein particles/fibers emerge from a source, a first electrode, kept at a certain, preferably constant, electric potential. By applying a counter electrode, a second electrode, kept at another certain, preferably constant, electrical potential, an electrical field exists. The particles/fibers will under the influence of this electrical field be directed toward the medical device.

Spray coating and dip coating are suitable alternatives to electrospinning.

In another embodiment of the present invention, the body of the medical device may be essentially made of a mixture of PTFE, such as Teflon^®, and oil. The mixture may be sintered in order to create a tube of expanded PTFE (ePTFE). After approximately half of the sintering process, the process may be temporarily interrupted, and a tube of e.g. steel or other material may enclose what will be the body part of the medical device, whereas another tube of e.g. steel may enclose a part which may be used as a shaft of a catheter. The tube enclosing the body part of the medical device may be of a larger diameter than the tube enclosing the shaft part, thereby allowing for the body part of the medical device to expand. The PTFE tube may be connected to a pressurization device and pressure may be applied. Subsequently,' the sinter process may be reassumed, thereby creating a catheter having a body part which may be expandable due to the applied pressure during the process and a part which may be non-expandable, the latter being applicable as a shaft. The membrane may further comprise an outer surface layer, which may be made of nanofibers, e.g. by electrospun nanofibers. Alternatively, the elastic material filling the interstices may provide an outer surface layer. The outer surface layer may be one which conforms to the shape of the membrane, i.e. expands with the membrane when the membrane is inflated and contracts when the membrane is deflated. The outer surface layer of the membrane may be essentially made from urethane.

It should be understood that the abovementioned outer surface layer need not be the outermost layer of the membrane/body of the medical device, for example a layer of hydrophilic polymer (e.g. polyacrylic acids and copolymers, polyethylene oxides, polyN-vinyl lactams such as polyvinyl pyrrolidone, etc.) may be provided as a coating on the outer surface layer in order to ensure a low-friction surface. Alternatively, a barrier layer may be provided as a coating on the outer surface layer in order to ensure that contact between the outer surface layer and blood is delayed until the medical device is in place. The barrier layer may be formed of a biodegradable polymer which dissolves or disintegrates. In embodiments of the invention, a low surface friction may be achieved by applying a hygroscopic material for the outer surface layer. Accordingly, once introduced into the patient's body, the hygroscopic material absorbs bodily fluid, resulting in a hydrophilic low-friction surface. A hygroscopic surface may for example be achieved with a polyurethane or a polyacrylic acid material.

Furthermore, the outer surface layer of the membrane may comprise pulverized carbonate, thereby creating crystals in the layer. If the membrane after nanospinning with pulverized carbonate in the filament is washed with e.g. acetic acid, the crystals will be dissolved in the acid, and the membrane will obtain a porosity corresponding to the porosity of carbonate. It is thereby possible to increase the porosity of the membrane.

The outer surface layer of the membrane may further comprise an acidic agent. Acidic agents may enhance the release of pharmaceutically active substances. The membrane may comprise such pharmaceutically active substances and/or these substances may be applied to the luminal side of the membrane after introduction of the balloon into the patient's body. As an example, the rate of nitric oxide (NO) liberation highly depends on the pH of the media. Thus, by addition of various amounts of an acid, the rate of NO liberation can be controlled. E.g. the half-life of NO liberation at pH = 5.0 is approximately 20 minutes whereas at pH = 7.4 the half-life is approximately 10 hours. As examples, Ascorbic Acid and Lactic Acid can be used as acidic agents for enhancing release of pharmaceutically active substances.

Nitric oxide releasing matrixes also may relax or prevent arterial spasm once the medical device is in place. Nitric oxide inhibits the aggregation of platelets and reduces smooth muscle proliferation, which reduces restenosis. When delivered directly to a particular site, it has been shown to prevent or reduce inflammation at the site where medical personnel have introduced foreign objects or devices into the patient.

In embodiments of the present invention, the membrane allows gas to diffuse from the lumen of the medical device to a surrounding tissue, but the membrane may be impermeable for liquid to diffuse from the lumen to the surrounding tissue. In other embodiments, the membrane may be permeable for liquid to diffuse from the balloon lumen to the surrounding tissue.

In a second aspect, the invention provides a catheter comprising an inflatable medical device for expansion in a body duct, the medical device defining a lumen and a membrane which essentially encloses the lumen, the membrane being adapted to expand by application of a pressure in the lumen, the membrane having a structure that allows gas and/or liquid to diffuse from the lumen to a surrounding tissue, and which prevents liquid from diffusing from the surrounding tissue into the lumen.

It should be understood, that the above described features may also be applicable to the inflatable medical device associated with the catheter.

The catheter may further comprise a shaft which may comprise a connector device for connecting the catheter to a pressurization device for applying a pressure to gas and/or liquid accommodated in the catheter. The shaft may be made of e.g. PTFE, such as Teflon, or other polymers. If the medical device is sintered of PTFE and oil, the shaft may be created in the same process. If the medical device comprises a body which comprises a framework of an essentially inelastic filament, the shaft may be added subsequently to the manufacture of the medical device.

In order to facilitate passage of the shaft to the treatment site along an often tortuous path, a hydrophilic layer may be applied to the outer surface layer. The hydrophilic layer may be provided as a separate layer of material. Alternatively, the outer surface may itself exhibit hydrophilic properties.

The connecting device may be adapted to be connected to a pressure bottle in order to receive pressure there from and/or it may be adapted to receive pressure from a syringe. As an example, a syringe comprising unmixed liquid and gas may be used. When ready for use, the liquid and gas may be mixed and the mixture may be injected into the shaft via the connecting device, thereby expanding the expanding the membrane. The gas and/or liquid may comprise e.g. nitric oxide, carbon oxide or oxygen. If being expanded by the pressure of a gas, the membrane may liberate gas particles to the surrounding tissue. As an example, the gas may comprise nitric oxide (NO) and/or N₂ (e.g. premixed in a pressure bottle), whereby nitric oxide may be liberated to the surrounding tissue, thereby relaxing or preventing arterial spasms, inhibiting the aggregation of platelets, reducing smooth muscle proliferation and/or preventing or reducing inflammations. For certain medical treatments, it is desired that nitric oxide is released into the body tissue in the gas phase immediately upon expansion of the membrane.

If being expanded by the pressure of a liquid, the membrane may liberate the liquid and/or gas particles dissolved in the liquid to the surrounding tissue. As an example the liquid may comprise nitric oxide either as gas particles or dissolved in e.g. water. Nitric oxide may thereby be transported to the surrounding tissue by diffusion or by water flow.

In a third aspect, the invention provides use of an expandable membrane in the preparation of a disposable medical device for the treatment of a cell disorder in a body duct, wherein the medical device defines a balloon lumen, which is essentially enclosed by said membrane, the membrane constituting a wall of the balloon and being permeable for a pharmaceutically active substance to diffuse from the lumen to a surrounding tissue, and wherein said pharmaceutically active substance is administered to a patient through permeation from the luminal side of the balloon to the exterior side of the balloon.

The treatment of cell disorder may be tissue relaxation in order to prevent inflammation, inhibition of aggregation of platelets, reduction of smooth muscle cell migration and proliferation, and enhancement of endotheliazation. Furthermore, the disposable medical device may be used for local relaxation with NO prior to surgical intervention for prevention of inflammation due to applied trauma.

It should be understood that the preparation of the medical device may comprise the use of the features of the abovementioned medical device and membrane.

Furthermore, the expandable membrane may comprise a perforated material, e.g. an elastic material being perforated by laser.

The preparation of the disposable medical device may comprise the use a membrane which is permeable for pharmaceutically active substances selected from the group of nitric oxide, carbon oxide and oxygen.

The pharmaceutically active substance may be provided to the balloon lumen by connecting the medical device to a pressurization device for applying a pressure to gas and or liquid accommodated in the medical device, the gas and/or liquid comprising the pharmaceutically active substance. The pressurization device may e.g. be in the form of a pressure bottle and/or a syringe or an infusion pump. The pharmaceutically active substance may be liberated to the surrounding tissue upon expansion of the membrane by the pressure of the gas and/or liquid.

In a forth aspect, the invention provides use of a perforated expandable membrane for the preparation of a balloon for intravascular administration of gaseous nitric oxide, the membrane essentially enclosing a lumen of the balloon, said membrane allowing gaseous nitric oxide to be delivered from said lumen to a surrounding body tissue.

In a fifth aspect, the invention provides a method for administration of gaseous nitric oxide during intravascular intervention, the method comprising the steps of: placing an expandable perforated balloon at a treatment site, the balloon essentially enclosing a balloon lumen; conveying the gaseous nitric oxide to said lumen; and forcing the gaseous nitric oxide to diffuse from the lumen to a surrounding body tissue.

In a sixth aspect, the invention provides a method of manufacturing an expandable balloon for use in angioplasty procedures, the method comprising: forming a first elastic layer onto a mandrel, the first elastic layer being permeable for gas and/or liquid to pass from an inwardly facing side of the layer, which faces the mandrel, to an outwardly facing side of the material; winding at least one essentially inelastic filament around said layer, whereby interstices are provided between portions of the at least one filament; filling said interstices with a second elastic layer, so as provide an outer surface of the balloon, the second elastic layer being permeable for gas and/or liquid to pass from an inwardly facing side of the layer to an outwardly facing side of the material; the first and second layers thereby providing a membrane, which is impermeable for liquid to pass from the outwardly facing side of the material to the inwardly facing side of the material, and which is permeable for gas to pass from the inwardly facing side of the material to the outwardly facing side of the material.

It should be understood that the features described above may also be applicable in relation to the preparation of a balloon for intravascular administration of gaseous nitric oxide, in relation to a method for administration of nitric oxide and in relation to a method of manufacturing the expandable balloon. Brief description of the drawings

Embodiments of the present invention will now be further described with reference to the drawings, in which:

Fig. 1 is a sectional view of a body of an inflatable medical device under preparation.

Fig. 2 is a sectional view of a body of an inflatable medical device under preparation.

Fig. 3 is an illustration of a catheter connected to a syringe.

Detailed description of the drawings

Fig. 1 shows a sectional view of a body of a medical device 1 under preparation. During the manufacture of the body 1, an inner layer of elastic material 2 is formed at a mandrel 3. Subsequently, an essential inelastic filament 4 is wound around the inner layer of elastic material 2.

Fig. 2 also shows a sectional view of a body of a medical device 1 under preparation. During the manufacture of the body 1, an inner layer of elastic material 2 is formed at a mandrel 3. Subsequently, an essential inelastic filament 4 is wound around the inner layer of elastic material 2, followed by application of an elastic material 5 filling the interstices between the inelastic filament portions 4.

Fig. 3 is an illustration of a catheter 10 connected to a syringe 11. The catheter 10 comprises a body 1, essentially constituted by an expanded membrane, and a shaft 12. The body 1 comprises a framework of essential inelastic filament 4 wound around an inner layer of elastic material (not shown). The interstices between the filament portions 4 are filled with an elastic material 5. The syringe 11 comprises unmixed liquid 13 and gas 14. The liquid 13 and the gas 14 are mixed by breaking the seal between them before injecting the mixture into the catheter 10.

Claims

1. An inflatable medical device for expansion in a body duct, the medical device defining a lumen and a membrane which essentially encloses the lumen, the membrane being adapted to expand by application of a pressure in the lumen, the membrane having a structure that allows gas and/or liquid to diffuse from the lumen to a surrounding tissue, and which prevents liquid from diffusing from the surrounding tissue into the lumen.

2. The balloon of claim 1, wherein the membrane essentially forms a body of the balloon.

3. The balloon of claim 1 or 2, wherein the membrane comprises an outer surface layer, the outer surface layer being made from nanofibers.

4. The balloon of claim 3, wherein the outer surface layer is essentially made from urethane.

5. The balloon of claim 3, wherein the outer surface layer comprises an acidic agent.

6. The balloon of claim 1, wherein the membrane is impermeable for liquid to diffuse from the lumen to the surrounding tissue.

7. The balloon of claim 1, wherein the membrane is permeable for liquid to diffuse from the lumen to the surrounding tissue.

8. The balloon of claim 2, wherein said body of the balloon comprises a framework formed by at least one inelastic filament wound around a circumference of the balloon, whereby interstices are provided between portions of the filament, and wherein said permeable membrane comprises an elastic material filling said interstices.

9. The balloon of claim 8, wherein said elastic material comprises a filament.

10. A catheter comprising an inflatable medical device for expansion in a body duct, the medical device defining a lumen and a membrane which essentially encloses the lumen, the membrane being adapted to expand by application of a pressure in the lumen, the membrane having a structure that allows gas and/or liquid to diffuse from the lumen to a surrounding tissue, and which prevents liquid from diffusing from the surrounding tissue into the lumen.

11. The catheter of claim 10, further comprising a shaft which comprises a connector device for connecting the catheter to a pressurization device for applying a pressure to gas and/or liquid accommodated in the catheter.

12. The catheter of claim 11, wherein the membrane is adapted to liberate gas particles to a surrounding tissue after inflation of the medical device by a pressure of the gas.

13. The catheter of claim 11, wherein the membrane is adapted to liberate liquid and/or gas particles dissolved in the liquid to a surrounding tissue after inflation of the medical device by a pressure of the liquid.

14. The catheter of claim 10, wherein the membrane is permeable for nitric oxide on gaseous form to diffuse from the lumen to the surrounding tissue.

15. The catheter of claim 10, wherein the membrane is permeable for nitric oxide on liquid form to diffuse from the lumen to the surrounding tissue.

16. Use of an expandable membrane in the preparation of a disposable medical device for the treatment of a cell disorder in a body duct, wherein the medical device defines a balloon lumen, which is essentially enclosed by said membrane, the membrane constituting a wall of the balloon and being permeable for a pharmaceutically active substance to diffuse from the lumen to a surrounding tissue, and wherein said pharmaceutically active substance is administered to a patient through permeation from the luminal side of the balloon to the exterior side of the balloon.

17. Use according to claim 16, wherein the expandable membrane comprises a perforated material.

18. The use of claim 16, wherein the preparation of the medical device comprises a step of preparing the membrane by forming a framework by at least one inelastic filament wound around a circumference of the balloon, whereby interstices are provided between portions of the filament, and filling said interstices with an elastic material constituting the membrane.

19. The use of claim 18, wherein said elastic material comprises a filament.

20. The use of claim 19, wherein the preparation of the medical device comprises a step of preparing an outer surface layer of the membrane of nanofibers.

21. The use of claim 20, wherein the preparation of the medical device comprises a step of preparing the outer surface layer of the membrane essentially of urethane.

22. The use of claim 20, wherein the preparation of the medical device comprises a step of loading the outer surface layer of the membrane with an acidic agent.

23. The use of claim 16, wherein the membrane is permeable to pharmaceutically active substances selected from the group of nitric oxide, carbon oxide and oxygen.

24. The use of claim 16, wherein the preparation of the medical device comprises a step of connecting a shaft to the medical device, said shaft comprising a connector device for connecting the medical device to a pressurization device for applying a pressure to gas and/or liquid accommodated in the medical device.

25. The use of claim 24, wherein the gas and/or liquid comprises the pharmaceutically active substance.

26. The use of claim 25, further comprising a step of liberating the pharmaceutically active substance to the surrounding tissue, after expanding the membrane by the pressure of the gas and/or liquid.

27. The use of claim 24, wherein the gas comprises nitric oxide.

28. The use of claim 24, wherein the liquid comprises nitric oxide.

29. Use of a perforated expandable membrane for the preparation of a balloon for intravascular administration of gaseous nitric oxide, the membrane essentially enclosing a lumen of the balloon, said membrane allowing gaseous nitric oxide to be delivered from said lumen to a surrounding body tissue.

30. A method for administration of gaseous nitric oxide during intravascular intervention, the method comprising the steps of:

- placing an expandable perforated balloon at a treatment site, the balloon essentially enclosing a balloon lumen;

- conveying the gaseous nitric oxide to said lumen;

- forcing the gaseous nitric oxide to diffuse from the lumen to a surrounding body tissue.

31. A method of manufacturing an expandable balloon for use in angioplasty procedures, comprising:

- forming a first elastic layer onto a mandrel, the first elastic layer being permeable for gas and/or liquid to pass from an inwardly facing side of the layer, which faces the mandrel, to an outwardly facing side of the material;

- winding at least one essentially inelastic filament around said layer, whereby interstices are provided between portions of the at least one filament;

- filling said interstices with a second elastic layer, so as provide an outer surface of the balloon, the second elastic layer being permeable for gas and/or liquid to pass from an inwardly facing side of the layer to an outwardly facing side of the material; the first and second layers thereby providing a membrane, which is impermeable for liquid to pass from the outwardly facing side of the material to the inwardly facing side of the material, and which is permeable for gas to pass from the inwardly facing side of the material to the outwardly facing side of the material.